Remote ischaemic conditioning and remodelling following myocardial infarction: current evidence and future perspectives.

Remote ischaemic conditioning (rIC) has demonstrated its effectiveness as a powerful cardioprotective tool in number of preclinical and limited clinical settings. More recently, ischaemic postconditioning given after an ischaemic event such as a myocardial infarction (MI) has shown not only to reduce infarct size but also to have beneficial effects on acute remodelling post-MI and to reduce the burden of heart failure and other detrimental outcomes. Building on this platform, repeated rIC over a number of days has the potential to augment the protective process even further. This review considers the current evidence base from which the concept of rIC in the setting of post-MI remodelling has grown. It also discusses the ongoing and planned clinical trials which are attempting to elucidate whether the protection imparted by rIC in the preclinical setting can be translated to the clinic and become a realistic weapon in the clinician's armoury to tackle acute remodelling and heart failure post-MI.

Effect of frailty on treatment, hospitalisation and death in patients with chronic heart failure.

BACKGROUND: Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. The natural history of frail patients with CHF is unknown. METHODS: Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median age 76 years, median NT-proBNP 1156 ng/L) attending a routine follow-up visit. Those with CFS > 4 were classified as frail. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. RESULTS: 206 patients (44%) were frail. Of 291 patients with HF with reduced ejection fraction (HeFREF), those who were frail (N = 117; 40%) were less likely to receive optimal treatment, with many not receiving a renin-angiotensin-aldosterone system inhibitor (frail: 25% vs. non-frail: 4%), a beta-blocker (16% vs. 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). By 1 year, there were 56 deaths and 322 hospitalisations, of which 25 (45%) and 198 (61%), respectively, were due to non-cardiovascular (non-CV) causes. Most deaths (N = 46, 82%) and hospitalisations (N = 215, 67%) occurred in frail patients. Amongst frail patients, 43% of deaths and 64% of hospitalisations were for non-CV causes; 58% of cardiovascular (CV) deaths were due to advancing HF. Among non-frail patients, 50% of deaths and 57% of hospitalisations were for non-CV causes; all CV deaths were due to advancing HF. CONCLUSION: Frailty in patients with HeFREF is associated with sub-optimal medical treatment. Frail patients are more likely to die or be admitted to hospital, but whether frail or not, many events are non-CV.

Circulating stromelysin-1 (MMP-3): a novel predictor of LV dysfunction, remodelling and all-cause mortality after acute myocardial infarction.

INTRODUCTION: Changes to cardiac matrix are central to ventricular remodelling after acute MI and matrix metalloproteinase expression is implicated in this process. We investigated the temporal profile of MMP-3 and its relationship to LV dysfunction and prognosis following AMI. METHODS: We studied 382 patients with AMI. Plasma MMP-3 was measured at 0-12, 12-24 h and for subsequent 24 h periods during admission. LV function (LVEF) was assessed by echocardiography pre-discharge and at a median of 148 days and clinical endpoints at a median of 313 days. RESULTS: MMP-3 peaked prior to discharge thus pre-discharge levels were used in analyses. MMP-3 was associated with patient age (p<0.001), creatinine (p<0.001) and was higher in males (p<0.001) and hypertensives (p<0.001). MMP-3 inversely correlated with LVEF at follow-up (p=0.043), was higher in subjects with LVEF <40% (p=0.017) and in subjects with increasing EDV (p=0.017) or ESV (p=0.007) compared to those in whom volumes fell between visits. In the 58 patients reaching the endpoint of death or heart failure, MMP-3 was higher (p<0.001). On Kaplan-Meier analysis, subjects with levels above optimum cut off identified via ROC curves were more likely to suffer a clinical event (p=0.037). CONCLUSION: MMP-3 is associated with left ventricular dysfunction, adverse left ventricular remodelling and prognosis after AMI.

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

Cardiotrophin-1 protects the human myocardium from ischemic injury. Comparison with the first and second window of protection by ischemic preconditioning.

BACKGROUND: There are reports suggesting that cardiotrophin 1 (CT-1) is cytoprotective. We investigated the cardioprotective effects of CT-1 on the human myocardium and compared this benefit with the early and delayed protection afforded by ischemic preconditioning (PC). METHODS: Right atrium specimens were prepared and incubated in buffer solution at 37 degrees C for 30 min stabilisation, before entering one of the three following studies. In study 1, muscles (n=6/group) were allocated to one of four groups: (i) aerobic control - incubated in oxygenated media for 210 min, (ii) ischemia alone - 90 min ischemia followed by 120 min reoxygenation, (iii) PC by 5 min ischemia-5 min reoxygenation before 90 min ischemia-120 min reoxygenation and (iv) CT-1 (1 nM) - 90 min ischemia-120 min reoxygenation with exposure to CT-1 throughout the protocol. In study 2, muscles (n=6/group) were allocated to one of four protocols as in study 1with the exception that were incubated for 24 h followed by 30 or 90 min ischemia-120 min reoxygenation on day 2. In study 3, the same groups were employed as in study 2 with the exception that only a 30-min period of ischemia was used and that CT-1 antibody (5 microg/ml) was added to all groups throughout the experimental protocol. Creatine kinase (CK, U/g wet wt.) leakage into the medium and MTT reduction (OD/mg wet wt.), an index of cell viability, were assessed at the end of the experiment. RESULTS: In study 1, a first window of cardioprotection was observed with PC (CK=4.39+/-0.34; MTT=0.58+/-0.03 vs. CK=7.11+/-0.4;MTT=0.32+/-0.02 in the ischemic alone group; P<0.001) but not with CT-1(CK=6.65+/-0. 67; MTT=0.31+/-0.03, P=NS vs. ischemia alone). In study 2, PC applied on day 1 was protective against 30-min ischemia (CK=3.28+/-0. 43; MTT=0.68+/-0.046, P<0.001 vs. ischemia alone) but not against 90-min ischemia (CK=7.13+/-0.66; MTT=0.24+/-0.03, P=NS vs. ischemia alone) induced on day 2 (second window). However, when the tissue was exposed to CT-1 for 24 h, protection was similar to that of PC when subjected to 30 min of ischemia (CK=2.95+/-0.71; MTT=0.77+/-0. 05, P=NS vs. PC) and greater than PC when subjected to 90 min of ischemia (CK=4.56+/-0.51; MTT=0.39+/-0.03, P=0.002 vs. PC). In study 3, the CT-1 antibody did not affect the protection induced by PC (CK=3.36+/-0.6; MTT=0.69+/-0.06) but it abolished the protection obtained with CT-1(CK=5.15+/-0.81; MTT=0.42+/-0.06, P=NS vs. ischemia alone group). CONCLUSIONS: CT-1 exhibits a significant protection of the human myocardium against ischemic injury when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the one obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.

Bradykinin B(2) receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men.

The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B(2) receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each P<0.0005 versus placebo). Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (P<0.0005) but had no effect on neurohormonal responses to perindoprilat. Our study indicates that the bradykinin B(2) receptor antagonist icatibant attenuates the short-term blood pressure-lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B(2) receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans.

Blood pressure response to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.

The effect of valvular regurgitation on plasma Cardiotrophin-1 in patients with normal left ventricular systolic function.

BACKGROUND: Cardiotrophin-1 (CT-1), a member of the interleukin-6 related cytokine family that act via the gp130 signalling pathway, has been shown to stimulate the assembly of sarcomeric units in series in cardiomyocytes resulting in eccentric hypertrophy, ventricular dilatation and finally loss of function. In situations of volume overload a similar form of eccentric hypertrophy occurs with time. AIMS: We hypothesised that plasma CT-1 would be raised in patients with significant mitral, tricuspid and/or aortic regurgitation (MR/TR or AR, respectively) when compared to those with no (or mild) valvular regurgitant lesion. METHODS: A novel competitive immunoluminometric assay using an in-house polyclonal antibody to amino acids 105-120 of the CT-1 sequence was developed. Seventy-eight patients (31 male, mean+/-S.D. age 63.5+/-17.9 years), all with normal left ventricular systolic function were studied. Results are expressed as mean+/-S.D. fmol/ml. RESULTS: Sixty-three subjects had no significant valvular lesion, seven had moderate/severe MR, nine had moderate/severe TR and four had moderate/severe AR. These subjects had CT-1 concentrations of 53. 3+/-23.2, 90.5+/-44.4, 72.6+/-43.8 and 48.4+/-24.4, respectively (P=0.02, ANOVA). Mean log CT-1 was higher in those with moderate/severe MR when compared to those without a significant regurgitant valvular lesion (P<0.03). The only predictor of moderate/severe MR was log CT-1 (P=0.004). CONCLUSION: These results suggest that plasma CT-1 is raised in those patients with moderate/severe MR in the presence of normal left ventricular systolic function. This secretion of CT-1 could potentially be the cause of ventricular dilatation and subsequent loss of contractile function in these patients. It also offers the intriguing possibility that plasma CT-1 could be used to monitor progression of mitral regurgitation biochemically.

Plasma N-terminal pro BNP and cardiotrophin-1 are elevated in aortic stenosis.

BACKGROUND: Echocardiography with Doppler examination of the aortic valve provides a very accurate assessment of the transvalvular gradient and is used to monitor progression of aortic stenosis (AS). Plasma brain natriuretic peptide (BNP) has been shown to correlate with end-systolic wall stress in patients with AS. AIM: We hypothesized that plasma N-terminal proBNP (NT proBNP) and a newly identified cytokine cardiotrophin-1 (CT-1), which has been shown to stimulate BNP production at a transcriptional level are elevated in patients with AS and correlate to the maximum trans-valvular aortic pressure gradient (TVPG). METHOD: We compared plasma NT proBNP and CT-1 in 15 AS patients [five males, mean age 79 years [range 60-94], mean TPVG 39.3 mmHg (20-100)] with 10 controls (five male, mean age 68 years [56-79]). Results are expressed as mean [ranges] and comparisons were by the Mann-Whitney test. RESULTS: NT proBNP levels were elevated in AS patients [252.9 fmol/ml (79.2-541.8)] when compared with the controls (157.2 fmol/ml [104.7-236.9], P<0.005). Also CT-1 levels were elevated in AS patients (57.3 fmol/ml [33-86.3] when compared with the controls [28.3 fmol/ml (6.9-48.3), P<0.0005]. Both NT proBNP and CT-1 levels were correlated to the TVPG (r=0.53 and r=0.65, P<0.05 and P=0.009, respectively). On best subset analysis the strongest correlate with TVPG was CT-1 (R2=38%). The addition of NT proBNP did not improve diagnostic accuracy (R2=39%). CONCLUSION: These results suggest NT proBNP and CT-1 levels increase in proportion to the TVPG and could potentially be used to monitor progression of disease non-invasively. These markers may also be useful to identify the optimum time for surgery in AS.

Prolonged stability of endogenous cardiotrophin-1 in whole blood.

Cardiotrophin-1 (CT-1) is a recently identified cytokine of the interleukin-6 (IL-6) family that signals through the gp130 signalling pathway. CT-1 may be of central importance to the pathogenesis of ventricular remodelling in patients with acute myocardial infarction (AMI) and therefore have clinical value in the identification of patients with impaired ventricular function. Central to the clinical use of CT-1 is in the in vitro stability of the peptide. Twelve subjects were recruited. A total of 25 mL of peripheral venous blood was collected into chilled polypropylene tubes containing EDTA and aprotinin and divided into 5 aliquots. One sample was spun in a prerefrigerated centrifuge (4 degrees C) at 3,000 rpm for 10 minutes and plasma separated and frozen at -70 degrees C immediately. Remaining samples were stored for 24 and 48 hours at room temperature or on ice. CT-1 in extracted plasma specimens was measured with a competitive chemiluminescent assay. The concentration of CT-1 in samples stored optimally was 43.1 +/- 6.05 fmol/mL. CT-1 levels for storage at room temperature compared with ice at the remaining time points were as follows: 24 hours, 41.5 +/- 5.76 v 37.5 +/- 8.66; and 48 hours, 42.6 +/- 6.28 v 41.0 +/- 5.42 fmol/mL. There were no significant changes in concentrations of CT-1 stored optimally or kept for up to 48 hours in aliquots of whole blood at room temperature or on ice. We conclude that CT-1 is stable in specimens of whole blood treated with EDTA and aprotinin and stored for up to 48 hours at room temperature or on ice, hence permitting its development in the routine clinical investigation of patients with heart failure.

Combination therapy with tirofiban and enoxaparin in acute coronary syndromes.

BACKGROUND: Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and enoxaparin, a low molecular weight heparin, have each been shown to be effective at reducing cardiac ischemic events compared to unfractionated heparin alone in separate trials of patients with unstable angina and non-Q-wave myocardial infarction. The combination of these agents may offer further therapeutic benefit. MATERIALS AND METHODS: Fifty-five patients with non-Q-wave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 microgram/kg/min i.v.) for 48-108 h coadministered with either enoxaparin (1 mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. adjusted to activated partial-thromboplastin time) (n=27) to evaluate pharmacokinetics, pharmacodynamics, and safety. The primary objective of the study was to investigate the effect of unfractionated heparin versus enoxaparin on the plasma clearance of tirofiban. RESULTS: Coadministration of tirofiban and enoxaparin was generally well tolerated. Plasma clearance of tirofiban was 176.7+/-59.8 and 187.5+/-81.8 ml/min, respectively, for enoxaparin and unfractionated heparin-treated patients (P=NS). The mean difference was well within the prespecified criterion for comparability. Administration of tirofiban with enoxaparin vs. unfractionated heparin resulted in lesser variability and a trend towards greater inhibition of platelet aggregation using 5 microM adenosine phosphate agonist. More patients achieved target inhibition of platelet aggregation >70% in the tirofiban and enoxaparin group (84% vs. 65%, P=0.19). Median bleeding time was 21 min for tirofiban and enoxaparin vs. > or =30 min for tirofiban and unfractionated heparin (P=NS). For a given level of inhibition of platelet aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9 min, P=0.02). Tirofiban plasma concentration and clearance were comparable whether coadministered with enoxaparin or unfractionated heparin. There were no major or minor bleeding events in either group by the TIMI criteria. INTERPRETATION: The more consistent inhibition of platelet aggregation and lower adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and unfractionated heparin support the therapeutic potential of combining these two agents. These data from the first clinical report of coadministration of a glycoprotein IIb/IIIa receptor antagonist and a low molecular weight heparin are consistent with prior data which show differential pharmacodynamic effects of enoxaparin and unfractionated heparin on platelet aggregation.

Improving long-term outcomes following coronary artery bypass graft or percutaneous coronary revascularisation: results from a large, population-based cohort with first intervention 1995-2004.

OBJECTIVE: To describe recent trends in outcome after first coronary revascularisation in routine clinical practice, with a focus on the influence of co-morbidity, demographics and ethnicity. DESIGN: Historical cohort study. SETTING: Leicestershire, UK (resident population 946 000). PATIENTS: All consecutive patients (n = 6068) after first-ever coronary revascularisation by coronary artery bypass graft surgery (CABG, n = 2520) or percutaneous coronary intervention (PCI, n = 3548) in the period between 1995-6 and 2003-4. OUTCOME MEASURES: Mortality (all-cause and cardiovascular), repeat revascularisation, unplanned readmission, acute myocardial infarction (MI), stroke and the combination of these outcomes. RESULTS: Among inpatients undergoing their first revascularisation, hospital co-morbidity increased significantly between 1995-6 and 2003-4. In contrast, operative outcomes improved, particularly among the PCI patients experiencing a two-year event-free survival of 83% in the latter period (2001-4), compared to just 73% in the earlier period (1995-8). After statistical adjustment for the temporal increase in preoperative co-morbidity and changing patient demographics, the rates of all-cause and cardiovascular mortality were similar after PCI when compared to CABG, generally less than 5% in the first two years following the index procedure. However, the risk of further revascularisation was much higher (10-fold) with index PCI. The adjusted risk for the need for further procedure was lower after PCI with a coronary stent (HR 0.61, 95% CI 0.49 to 0.74), compared to without, a coronary stent. Except for the risk of readmission, outcome was independent of patients' ethnicity, and for women the risk of death was lower (HR 0.73, 95% CI 0.61 to 0.87). CONCLUSIONS: On a background of increasingly complex preoperative profile, outcomes after first coronary revascularisation procedure seem to have improved in routine clinical practice since the 1990s, and compare well to those seen in clinical trials. In contemporary, routine clinical practice survival is very similar after CABG or PCI, but rate of further revascularisation procedure remains much higher after PCI, despite increasing use of coronary stenting.

Glucose and haemoglobin in the assessment of prognosis after first hospitalisation for heart failure.

OBJECTIVE: To examine the relationship with outcome of plasma haemoglobin and glucose concentrations, measured soon after first hospital admission with chronic heart failure (CHF), in standard clinical practice. METHODS AND RESULTS: Hospital records of 528 patients (43% women, mean age 70 years) with first hospital admission for CHF were reviewed. During follow up (mean 1257 days, range 520-1800), 240 (45%) patients died. On admission, 140 of 528 (27%) and at discharge 179 of 472 survivors (38%) were receiving treatment for diabetes. World Health Organization criteria for anaemia were met by 39% of men and 43% of women. Lower haemoglobin (hazard ratio 0.879, 95% confidence interval (CI) 0.828 to 0.933, p < 0.0001) and higher plasma glucose (hazard ratio 1.034, 95% CI 1.008 to 1.061, p = 0.009) had univariate association with all-cause mortality. On multivariate analysis, compared with patients with a normal haemoglobin for their sex, hazard ratio was 1.415 (95% CI 1.087 to 1.841, p = 0.010) for those with low haemoglobin. All-cause mortality fell linearly for haemoglobin up to 159 g/l, above which mortality increased. Glucose above the highest quartile (> 10 mmol/l) was an independent predictor of mortality (hazard ratio 1.966, 95% CI 1.376 to 2.810, p = 0.0002). In survivors of the index admission the association between glucose and mortality was linear, the relationship being stronger for patients without diabetes. CONCLUSIONS: Lower haemoglobin and higher plasma glucose are associated with all-cause mortality in CHF. Higher glucose is associated with mortality irrespective of diabetic status.

Ethnicity and variation in prognosis for patients newly hospitalised for heart failure: a matched historical cohort study.

OBJECTIVES: To compare mortality and factors predictive for outcome in age matched white and South Asian cohorts after first admission for heart failure. DESIGN: Matched historical cohort study. SETTING: One National Health Service trust comprising three acute care hospitals. PARTICIPANTS: 176 South Asian (mean age 68 (10) years, 45% women) and 352 age and sex matched white (70 (11) years, 42% women) patients hospitalised for the first time with heart failure. MAIN OUTCOME MEASURES: All cause survival, measures of disease severity, and the association of clinical variables with outcome. RESULTS: Compared with white patients, South Asian patients had similar rates of prior coronary heart disease but more often had prior hypertension (45% v 33%, p = 0.006) and diabetes (46% v 18%, p < 0.0001). Atrial fibrillation (15% v 31%, p = 0.0002) and prior diuretic use (39% v 48%, p = 0.041) were less common among South Asians. Left ventricular function was more often preserved (38% v 23%, p = 0.002) and less often severely impaired (18% v 28%, p = 0.025) among South Asians. During follow up (range 520-1880 days) 73 of 176 (41.2%) South Asian and 167 of 352 (47.4%) white patients died. South Asian ethnicity was associated with lower all cause mortality (odds ratio 0.71, 95% confidence interval 0.53 to 0.96, p = 0.02). Other predictors of outcome (admission age, lower systolic blood pressure, higher creatinine, higher plasma glucose, and lower haemoglobin) were similar in each cohort. CONCLUSIONS: At first hospitalisation, heart failure appears less advanced in South Asians, among whom diabetes and hypertension are more prevalent. Survival is better for South Asian than for white patients. Higher glucose and lower haemoglobin at admission provide useful prognostic information in heart failure.

The rational use of beta-adrenoceptor blockers in the treatment of heart failure. The changing face of an old therapy.

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of antagonists of the adrenergic beta-receptor (beta-blockers) in heart failure has been the subject of debate for many years. Data from studies of the therapeutic use of beta-blockers in patients following acute myocardial infarction suggest that in this circumstance these agents confer at least as much benefit to patients with heart failure as they do to those without. Similarly retrospective analysis of a number of the studies of angiotensin converting enzyme (ACE) inhibitors in heart failure suggest a greater effect of the combination of beta-blocker with ACE inhibitor compared with ACE inhibitor alone. The results of recent prospective, placebo-controlled studies of the addition of beta-blocker to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect. beta-blocker therapy in these studies was well tolerated and in addition to improved mortality, beta-blocker therapy is associated with improved morbidity in terms of progressive heart failure and numbers of hospitalizations. Initiation of beta-blocker therapy in heart failure may be associated with deterioration of cardiac function in the short term. Treatment should be started at a low dose of beta-blocker with slow up-titration in a number of steps over several weeks. In spite of the established benefits of ACE inhibition in patients with heart failure, this treatment is under-utilized. Part of this shortfall is due to physicians' perceptions regarding potential unwanted effects of ACE inhibition. Perceptions regarding unwanted effects of beta-adrenoceptor blocker therapy are likely to be at least as great. While beta-blockade represents a welcome addition to the therapeutic armoury of physicians caring for patients with heart failure, initiation and stabilization of beta-adrenoceptor blocker therapy should be undertaken under specialist supervision.

The clinical pharmacology of ACE inhibitors: evidence for clinically relevant differences?

1. Potential differences among ACE inhibitors include pharmacokinetic and pharmacodynamic factors. The presence of a sulfhydryl group conferring antioxidant properties, the administration as a pro-drug to delay the onset and prolong the duration of haemodynamic effects, and the route of elimination are examples of possible differences. 2. Adverse effects of ACE inhibitors may be mediated by effects on bradykinin metabolism at tissue sites, which may be separable from haemodynamic responses mediated largely by angiotensin II withdrawal. 3. Clinically important differences between ACE inhibitors in their adverse event profile have yet to be proven. Evidence is emerging that plasma ACE inhibition and haemodynamic responses are separable, and this may indicate the potential for other organ-specific effects to differ among ACE inhibitors. 4. At present, however, the greatest distinguishing features for one compound vs another are the time to onset and the duration of action, which determine the frequency of administration.