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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.

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

To assess the vascular and cardiac response to NO (nitric oxide) synthase (NOS) blockade in vivo, Wistar-Kyoto rats (WKY) were treated for 3 wk with N G-nitro-l-arginine methyl ester (l-NAME; 10 mg ⋅ kg−1 ⋅ day−1).l-NAME treatment induced hypertension that was associated with increased plasma renin activity. Flow cytometry cell cycle DNA analysis showed that aortic vascular smooth muscle cells (VSMC) froml-NAME-treated WKY had a significantly higher polyploid population compared with WKY controls. Using organ bath experiments, we have shown that aortic rings froml-NAME-treated WKY have an increased contractile response to phenylephrine and impaired relaxation to carbachol compared with control rings. NOS blockade in vivo caused a significant increase in cardiac and left ventricular hypertrophy. Northern mRNA analysis of the myocardium showed thatl-NAME treatment caused reexpression of the fetal skeletal α-actin isoform without alterations in collagen type I expression, a pattern indicating true hypertrophy of the cardiomyocytes. These studies provide further insight to confirm that NO deficiency in vivo results in the development of vascular and cardiac hypertrophy.

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

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.

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

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

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

Abstract The insertion (I)/deletion (D) polymorphism of the human angiotensin-converting enzyme gene has emerged as a genetic risk factor for ischemic heart disease. However, the functional consequences of this polymorphism in humans are not known. Ten normotensive men with the DD genotype and 10 with the II genotype participated in a study in which pressor responses to stepwise infusions of incremental doses of angiotensin I (Ang I) and Ang II and Ang II production during Ang I infusion were measured. Pressor responses were expressed as PD 20 , which reflects the angiotensin dose required to raise mean blood pressure by 20 mm Hg. The PD 20 for Ang I in subjects with the DD genotype was significantly lower than that in II genotype subjects (8.8 versus 14.8 ng/kg per minute, P =.0091), whereas the PD 20 for Ang II between the two groups did not differ significantly. The ratio of PD 20 for Ang I and Ang II in DD subjects was significantly lower than that in II subjects (0.85 versus 0.96, P =.0452), and the venous levels of Ang II during Ang I infusion in DD subjects were significantly higher than those in II subjects ( P

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 …

The new, long acting converting enzyme inhibitor enalapril was given to 26 patients with moderate to severe heart failure. In 23 cases the mean systolic blood pressure fell from 120 (SD 22) to 108 (25) mm Hg without adverse effects. Profound hypotension with severe bradycardia and sweating, however, occurred in three patients, most pronounced two to four hours after the first dose. The haemodynamic and biochemical changes in these patients were similar to those seen in patients with severe symptomatic hypotension after the first dose of the converting enzyme inhibitor captopril, except that with enalapril the changes occurred later and were longer lasting. Evidence of myocardial damage and reversible renal failure was seen in one patient, and acute reversible deterioration in renal function occurred in one other. In patients with heart failure converting enzyme inhibitors should be administered initially under strict medical supervision with appropriate facilities available for dealing with occasional profound hypotension.

The effect of sodium depletion on the dose-response relationships of angiotensin II to aldosterone and blood pressure was studied. Arterial plasma angiotensin II and aldosterone and arterial blood pressure were measured before and during the incremental infusion of angiotensin II into sodium-replete and sodium-deplete subjects. Sodium depletion caused a distinct steepening of the angiotensin Il-aldosterone dose-response curves in four of five subjects and a concurrent diminution in the pressor effect of angiotensin II. Administration of angiotensin II did not demonstrably alter the half-life of aldosterone. Sodium depletion did not change the plasma concentrations of sodium or potassium, but it was accompanied by a significant increase in plasma levels of 11-hydroxycorticosteroids and magnesium. The contrasting effects of sodium depletion on the aldosterone and the pressor dose-response curves favored sodium retention. These results are consistent with an important role for the renin-angiotensin system in the control of aldosterone secretion in man.

The effect of the converting enzyme inhibitor captopril as long term treatment was investigated in 14 patients with severe congestive heart failure in a double blind trial. Captopril reduced plasma concentrations of angiotensin II and noradrenaline, with a converse increase in active renin concentration. Effective renal plasma flow increased and renal vascular resistance fell; glomerular filtration rate did not change. Serum urea and creatinine concentrations rose. Both serum and total body potassium contents increased; there were no long term changes in serum concentration or total body content of sodium. Exercise tolerance was appreciably improved, and dyspnoea and fatigue lessened. Left ventricular end systolic and end diastolic dimensions were reduced. There was an appreciable reduction in complex ventricular ectopic rhythms. Adverse effects were few: weight gain and fluid retention were evident in five patients when captopril was introduced and two patients initially experienced mild postural dizziness; rashes in two patients did not recur when the drug was reintroduced at a lower dose; there was a significant reduction in white cell count overall, but the lowest individual white cell count was 4000 X 10(6)/l. Captopril thus seemed to be of considerable value in the long term treatment of severe cardiac failure.

Neuroendocrine activation in acute myocardial infarction (AMI) may have important physiological consequences for myocardial perfusion and function. We measured plasma angiotensin II in 60 patients with AMI within 6 hours of pain and on days 1-3 and day 10. On admission, AII was normal at 9.9 + 1.3 pmol/l (normal range 2-12 pmol/l). At day 3, AII rose markedly to 77.5 + 25.0 in those with heart failure (group 1, n = 13); but AII also rose in uncomplicated patients (group 2, n = 47) to 27.8 + 4.0 (p less than 0.001). At day 10, levels of AII remained high, especially in group 1 (50.5 + 22.2 vs 6.1 + 1.5, p less than 0.005). Thus neuroendocrine activation, present early in AMI, is seen in both uncomplicated infarcts and in those developing heart failure. Angiotensin II mediated vasoconstriction perhaps enhanced by catecholamines could have deleterious effects on myocardial function and perfusion, and indicates the potential for angiotensin-converting enzyme inhibitors in early AMI.

Activation of the renin-angiotensin system in acute myocardial infarction may have important haemodynamic consequences. The effects of captopril were assessed in nine patients with acute left ventricular failure complicating myocardial infarction. Plasma angiotensin II was elevated at 16.8 (3.6) pmol/l (mean [SE]) including high levels in three of four patients in the absence of any previous therapy, including diuretics. Repeated low doses of captopril were administered to reduce pulmonary capillary wedge pressure less than 14 mm Hg or to a maximum total dose of 25 mg. Right atrial pressure fell from 12.4 (0.9) to 9.4 (0.7) mm Hg p less than 0.001, pulmonary arterial pressure from 32.7 (3) to 26.4 (2.2) p = 0.01, and pulmonary capillary wedge pressure from 25.7 (2.9) to 19.9 (2.2) p = 0.01. Despite a fall in systemic vascular resistance from 1,540 (110) to 1,330 (76) dyn/s/cm5, and mean arterial pressure from 84.8 (3.9) to 76.7 (2.7) p = 0.001, changes in cardiac output were small: 3.8 (0.3) to 4.2 (0.3) NS. Angiotensin II fell in all patients even after only 3.125 mg to a mean of 3.6 (1.0). These improvements occurred whether basal angiotensin II was elevated or normal, and in the presence or absence of diuretic therapy. At 24 hours, seven patients received captopril in the maximum titrated dose of the previous day. Haemodynamic changes at one hour were of similar magnitude to those during incremental dosing. These results suggest that reduction of angiotensin II exerts beneficial haemodynamic effects in heart failure complicating acute myocardial infarction.

The extent of neuroendocrine activation, its time course, and relation to left ventricular dysfunction and arrhythmias were investigated in 78 consecutive patients with suspected acute myocardial infarction. High concentrations of arginine vasopressin were found within six hours of symptoms, even in the absence of myocardial infarction (n = 18). Plasma catecholamine concentrations also were highest on admission, whereas renin and angiotensin II concentrations rose progressively over the first three days, not only in those with heart failure but also in patients with no clinical complications. Heart failure, ventricular tachycardia, and deaths were associated with extensive myocardial infarction, low left ventricular ejection fraction, and persistently high concentrations of catecholamines, renin, and angiotensin II up to 10 days after admission, whereas in uncomplicated cases concentrations had already returned to normal.

Spontaneous development of malignant phase hypertension in transgenic Ren-2 rats. Spontaneous development of malignant phase hypertension in TGR(mREN2)27 heterozygotes occurs as a consequence of crossing TGR(mREN2)27 homozygotes with Edinburgh Sprague-Dawley rats. Similarities to human malignant phase hypertension are seen with an accelerated rise in blood pressure, fibrinoid necrosis of renal afferent arterioles, renal failure and evidence of renin-angiotensin system activation. It appears that introduction of an additional genetic factor or factors into a monogenic model of hypertension results in malignant phase hypertension.

A non-sulfhydryl-containing inhibitor of angiotensin-converting enzyme (MK421) was given as a single dose in a randomised double-blind cross-over trial using 20 mg and 5 mg of MK-421 or matched placebo to nine normotensive volunteers receiving a sodium intake of 150 mmol (mEq) daily. The two dosages of MK-421 caused similar, significant falls in supine and standing blood pressure, which were maximum four to six hours after dosing (9.5-11.0% fall). With this fall in blood pressure there was a significant fall in activity of angiotensin-converting enzyme and in concentrations of plasma angiotensin II and aldosterone and a rise in plasma renin activity. Placebo caused no significant change in blood pressure or blood measurements. The study showed that MK-421 inhibits angiotensin-converting enzyme activity and lowers blood pressure in normotensive subjects. It strongly suggested that the renin system plays an important part in maintaining blood pressure in normotensive subjects receiving normal sodium intake. The results also suggest that this non-sulfhydryl-containing converting-enzyme inhibitor will be an effective blood-pressure-lowering drug in patients with blood pressure. A single dose of 5 mg was as effective at lowering blood pressure as a single dose of 20 mg.

Enalapril maleate (MK421), a new inhibitor of angiotensin converting enzyme, in single daily doses of 1.25-40 mg was assessed in five patients with hypertension and renal artery stenosis. Only small falls in plasma angiotensin II concentrations were seen at doses less than 10 mg; even with 10 and 20 mg, angiotensin II concentrations had risen again 24 hours from the last dose. During long-term treatment with 10-40 mg daily all patients achieved good blood-pressure control. No significant changes of body sodium or potassium values were seen. The drug was well tolerated with no serious side effects. These findings are evidence of the efficacy and acceptability of enalapril in the medical management of hypertension with renal artery stenosis.

Dose-response curves relating plasma angiotensin II (AII) concentration during AII infusion to blood pressure (BP), to plasma aldosterone, and to plasma 18-hydroxycorticosterone were compared in normal subjects and in patients with essential hypertension, Conn's syndrome, and nontumorous hyperaldosteronism. The BP response was steeper than normal in patients with Conn's syndrome and essential hypertension. Before infusion, mean plasma aldosterone concentration was approximately four-fold higher in Conn's syndrome than in the normal group, while that of 18-hydroxycorticosterone was ninefold higher. Neither increased significantly during AII infusion. In essential hypertension, both corticosteroids were within the normal range, but their responses to AII infusion were greater than normal. In the three subjects with non-tumorous hyperaldosteronism, plasma aldosterone and 18-hydroxycorticosterone concentrations were raised, and their responses to AII infusion resembled those found in essential hypertension and were different from those found in Conn's syndrome. This suggests that nontumorous hyperaldosteronism is not a variant of Conn's syndrome. In the response to AII and in other ways, it is indistinguishable from essential hypertension.

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.

The case is reported of a young woman with severe hypertension, unilateral renal artery stenosis, variously normal or marginally high plasma concentrations of active renin, angiotensin II, aldosterone, sodium, and potassium; and normal total exchangeable and total body sodium and potassium. Arteriograms and ureter catheterization showed the stenosis to be severe, but the unstimulated renal vein renin and angiotensin II differential to be modest. Captopril caused an initial fall in angiotensin II and arterial pressure. During prolonged captopril treatment, plasma angiotensin II and aldosterone remained depressed; exchangeable and total body sodium and potassium were unaltered. Blood pressure fell further to normal levels during prolonged captopril treatment, while subsequent surgical correction of the renal artery stenosis was curative; absolute values of blood pressure and plasma angiotensin II were similar in both situations. The findings support, without proving, the concept that chronic modest elevation of angiotensin II may be responsible for sustained hypertension in unilateral renal artery stenosis. Patients of this type contrast sharply with those, also with severe renal artery stenosis or occlusion, who have gross elevation of renin, angiotensin II, and aldosterone, with sodium and potassium deficiency. Captopril or surgery are effective in both syndromes, but the manner of response to treatment differs markedly.

The effect of the converting enzyme inhibitor captopril on arterial pressure, the components of the renin-angiotensin-aldosterone system, and body sodium and potassium content was studied in eight hypertensive patients with renal artery stenosis and, in conjunction with diuretics, in seven patients with hypertension unresponsive to previous treatment. Two hours after the first dose, captopril caused significant falls in systolic and diastolic pressures, plasma angiotensin II, and aldosterone, with converse increases in angiotensin I and both active and total renin; the initial fall in diastolic pressure was significantly related to the drop in plasma angiotensin II. The biochemical changes were sustained during prolonged treatment, even when diuretics were added. One untreated patient with renal artery occlusion had severe secondary aldosterone excess, was sodium and potassium depleted, and severely hyponatraemic and hypokalaemic; captopril restored blood pressure, plasma electrolyte concentrations, and exchangeable sodium and total body potassium to normal. In one man with renal artery stenosis and overall renal impairment captopril led to sodium retention, and blood pressure did not fall until a diuretic was added. In the remaining patients with renal artery stenosis, pretreatment renin, angio tensin II, and aldosterone concentrations were either normal or only modestly raised, and plasma electrolyte concentrations and body content of sodium and potassium were normal. Captopril alone controlled arterial pressure in all, three cases showing a gradual fall of pressure over the first six weeks of treatment; no significant changes in exchangeable sodium or total body potassium were seen. The group of patients with previously intractable hypertension were all controlled with a combination of captopril and diuretic.

The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose, or with H142 at 1.0 or 2.5 mg/kg/h, for 30 min while supine and thereafter with dextrose for 1.5 h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after H142 infusion was stopped. In contrast, total renin concentration as measured by radioimmunoassay rose while ANG I and II fell, subsiding after H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited: plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.

The determination of the 2-keto-3-deoxyoctonic acid (KDO) content of a lipopolysaccharide obtained from Escherichia coli ATCC 12408 using the thiobarbituric acid and semicarbazide methods for its estimation points to the presence of a KDO trisaccharide unit in the structure. On partial hydrolysis of the lipopolysaccharide by the method of Painter, using polystyrene sulphonic acid, up to 60% of the KDO was lost. A core oligosaccharide, with a molecular weight in the region of 3500 to 5000 and containing heptose, glucose, galactose, KDO and phosphorus in the molar ratio of 2:1.44:0.6:0.3:1.3, was isolated on fractionation of the dialysate on Sephadex G-15. Sodium borohydride reduction of the oligosaccharide results in the loss of both reducing power and KDO, indicating a linear-type structure with KDO only at the reducing end. Removal of phosphate from the oligosaccharide had no significant effect on its molecular weight. Periodate oxidation, followed by borohydride reduction, and methylation studies showed the presence of certain structural features similar to those already found for the core region of lipopolysaccharides from other gram-negative bacteria.

The angiotensin converting-enzyme inhibitor captopril was used as long-term preoperative treatment in a series of hypertensive patients with unilateral renal arterial disease. There were immediate and sustained falls in plasma angiotensin II and aldosterone concentrations, with converse increases in circulating renin and angiotensin I. In patients with sodium and potassium deficiency and secondary aldosterone excess before treatment captopril corrected the sodium and potassium deficits; in these cases the initial hypotensive response was profound but the later effect was less pronounced. When sodium and potassium state was initially normal it remained unchanged during captopril treatment, while the full hypotensive effect took up to three weeks to be attained. The immediate, but not long-term, falls in arterial pressure with captopril were proportional to the immediate decrements of plasma angiotensin II. Nevertheless, while the immediate blood-pressure reduction with captopril variously overestimated and underestimated the eventual surgical response, the absolute blood-pressure values during long-term captopril related well with those after operation. Pretreatment plasma renin and angiotensin II concentrations, while closely predicting the immediate captopril response, are fallible guides to surgical prognosis. In contrast, long-term treatment with converting-enzyme inhibitors may provide an accurate indication of surgical outcome.

Pressor doses of infused norepinephrine (NE) (mean pressure, +20 mm Hg) or angiotensin II (AII) (diastolic pressure, +20 mm Hg) and corresponding blood levels of NE or AII were assessed in 12 young normal subjects under basal conditions (study A), during slow calcium infusion (0.034 mg/kg/min) started 60 min previously (study C), and following 2 weeks of treatment with the Ca antagonist nifedipine, 50 mg/day (study D). Control values of blood pressure, 24-h urinary sodium, plasma NE, epinephrine, AII, and renin activity did not differ among the three studies. Plasma Ca was higher during study C than during studies A and D [10.7 +/- 0.8 (+/- SD) versus 9.1 +/- 0.3 mg/dl; p less than 0.01]. Plasma NE or AII levels obtained during NE or AII infusion as well as the pressor doses of AII were not modified by concomitant Ca infusion or following nifedipine. However, compared with basal conditions, the NE pressor dose tended to be decreased slightly during Ca infusion (106 +/- 71 versus 77 +/- 38 ng/kg/min; difference not significant) and was increased markedly following nifedipine (178 +/- 87 ng/kg/min; p less than 0.05). A control infusion of Ca alone (study B) during 120 min did not modify blood pressure or plasma renin and NE levels. Our observations suggest that in normal humans, inhibition of cellular Ca transport may predominantly affect the noradrenergic control mechanism, whereas angiotensinogenic cardiovascular regulation may be less dependent.