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.

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.

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.

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.

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.

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.

Prognosis for patients newly admitted to hospital with heart failure: survival trends in 12 220 index admissions in Leicestershire 1993-2001.

OBJECTIVE: To examine rates of, prognosis following, and the influences on first hospital admission with heart failure in Leicestershire during 1993-2001. DESIGN: Historical cohort study using record linked discharge and mortality data. SETTING: Leicestershire, England. PATIENTS: 12 220 individual patients newly hospitalised with heart failure between 1 April 1993 and 31 March 2001. MAIN OUTCOME MEASURES: 30 day and one year survival, temporal trends in survival, and the influence on prognosis of age, sex, comorbidity, social deprivation, and year of hospital admission. METHODS AND RESULTS: Between 1993/94 and 2000/01, rates of first hospitalisation increased by 62%, from 29 to 47/10 000 population, confined largely to those aged > 65 years. Rates did not increase after 1998. Median age at presentation increased from 74 years in 1993/94 to 77 years in 2000/01 for men but was unchanged (80 years) for women. Overall one and five year survival was 57% and 27%, respectively. There was a 43-45% increase in risk of death for each decade of age at admission and a 14-17% increase associated with male sex. There was a clear influence on outcome of comorbidity but no influence of social deprivation score. Both one month and one year survival were lower for patients whose first heart failure admission was concomitant with acute myocardial infarction. Between 1993/94 and 2000/01 postdischarge cardiovascular survival improved by 50% (p < 0.001). CONCLUSIONS: Rates of first hospital admission with heart failure reached a plateau in the late 1990s. Case fatality rates remain high and prognosis poor, in particular for those of increasing age, for men, and for patients with concomitant acute myocardial infarction. However, clear trends to improved survival were seen over this time.

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.

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.

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.

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.

Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina.

OBJECTIVE: To compare circulating concentrations of N terminal pro-brain natriuretic peptide (N-BNP) and cardiotrophin 1 in stable and unstable angina. DESIGN AND SETTING: Observational study in a teaching hospital. PATIENTS: 15 patients with unstable angina, 10 patients with stable angina, and 15 controls. MAIN OUTCOME MEASURES: Resting plasma N-BNP and cardiotrophin 1 concentrations. RESULTS: N-BNP concentration (median (range)) was 714 fmol/ml (177-3217 fmol/ml) in unstable angina, 169.5 fmol/ml (105.7-399.5 fmol/ml) in stable angina (p = 0.005 v unstable angina), and 150.5 fmol/ml (104. 7-236.9 fmol/ml) in controls (p < 0.0001 v unstable angina; NS v stable angina). Cardiotrophin 1 concentration was 142.5 fmol/ml (42. 2-527.4 fmol/ml) in unstable angina, 73.2 fmol/ml (41.5-102.1 fmol/ml) in stable angina (p < 0.05 v unstable angina), and 27 fmol/ml (6.9-54.1 fmol/ml) in controls (p < 0.0005 v stable angina; p < 0.0001 v unstable angina). Log cardiotrophin 1 correlated with log N-BNP in unstable angina (r = 0.93, p < 0.0001). CONCLUSIONS: Both circulating N-BNP and cardiotrophin 1 are raised in unstable angina, while cardiotrophin 1 alone is raised in stable angina. The role of cardiotrophin 1 and the relation between cardiotrophin 1 and N-BNP in myocardial ischaemia remain to be defined.

Profile of plasma N-terminal proBNP following acute myocardial infarction; correlation with left ventricular systolic dysfunction.

AIMS: The aims of this study were to describe the temporal pattern of plasma N-terminal pro-brain natriuretic peptide, to examine the optimum time of sampling and to compare plasma N-terminal pro-brain natriuretic peptide to clinical criteria in terms of identification of impaired left ventricular systolic function following acute myocardial infarction. METHODS AND RESULTS: Measurements of N-terminal pro-brain natriuretic peptide were made in 60 patients at 14-48 h, 49-72 h, 73-120 h, 121-192 h following myocardial infarction and at 6 weeks in survivors. Left ventricular wall motion index was assessed during hospitalization (WMI-1) and at 6 weeks (WMI-2). N-terminal pro-brain natriuretic peptide levels were elevated at all time points, to a greater extent in anterior compared to inferior infarction (P < 0.05). A biphasic profile of plasma concentration was observed in anterior infarction with peaks at 14-48 h and 121-192 h. This was sustained at 6 weeks. N-terminal pro- brain natriuretic peptide at 73-120 h was the best independent predictor of WMI-1 (P < 0.005). N-terminal pro-brain natriuretic peptide was higher at all times in patients who received ACE inhibitor therapy compared to those who did not (P < 0.005). N-terminal pro-brain natriuretic peptide at 73-120 h (R(2) = 17.7%, P = 0.005) and previous myocardial infarction (R(2) = 5.3%, P < 0.05) were independent predictors of poor outcome (WMI-2 < or = 1.2 or death by 6 weeks). CONCLUSIONS: A biphasic pattern of plasma N-terminal pro-brain natriuretic peptide is seen after anterior myocardial infarction. Plasma level is strongly correlated to wall motion index soon after and remote from acute myocardial infarction. Plasma N-terminal pro-brain natriuretic peptide measured later in hospitalization better predicts poor outcome following myocardial infarction than when it is measured in the immediate post infarction period.

Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction.

Cardiotrophin-1 (CT-1) is a cytokine that has been implicated as a factor involved in myocardial remodelling. The objective of the present study was to establish the relationship between circulating levels of CT-1 and measures of left ventricular size and systolic function in patients with heart failure. We recruited 15 normal subjects [six male; median age 60 years (range 30-79 years)] and 15 patients [11 male; median age 66 years (range 43-84 years)] with a clinical diagnosis of heart failure and echocardiographic left ventricular systolic dysfunction (LVSD). Echocardiographic variables (left ventricular wall motion index, end-diastolic and -systolic volumes, stroke volume, fractional shortening) and plasma CT-1 levels were determined. In patients with LVSD [median wall motion index 0.6 (range 0.3-1.4)], CT-1 was elevated [median 110.4 fmol/ml (range 33-516 fmol/ml)] compared with controls [wall motion index 2 in all cases; median CT-1 level 34.2 fmol/ml (range 6.9-54.1 fmol/ml); P<0.0001]. Log CT-1 was correlated with log wall motion index (r=-0.76, P<0.0001), log left ventricular end-systolic volume (r=0.54, P<0.05), stroke volume (r=-0.60, P=0.007) and log fractional shortening (r=-0.70, P=0.001). In a multivariate model of the predictors of log wall motion index, the only significant predictor was log CT-1 (R(2)=56%, P=0.006). This is the first assessment of the relationship between plasma CT-1 levels and the degree of LVSD in humans, and demonstrates that CT-1 is elevated in heart failure in relation to the severity of LVSD.

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.

T-ceIl recognition of discrete regions of the thrombolytic drug streptokinase.

Streptokinase (SK) is a bacterial protein used clinically as a thrombolytic agent in humans. Administration of SK causes a rapid increase in the frequency of anti-SK T cells and the titre of specific anti-SK antibodies that, on subsequent administration of SK, may neutralize the activity of the drug or elicit allergic-type reactions. By locating and modifying the immunogenic T-cell epitopes within the SK protein, it is possible that an agent with reduced immunogenicity but equal efficacy may be produced. We have investigated the T-cell epitopes within SK using nine non-overlapping, recombinant peptide fragments of SK. We investigated the proliferative T-cell response of peripheral blood mononuclear cells obtained from patients before and 6 days after administration of SK for myocardial infarction. We also examined the response of cultured anti-SK T-cell lines derived from patients 6 days after treatment with SK. Before administration of SK, peripheral blood mononuclear cells from six of nine patients showed a proliferative response to SK. The response was significantly higher 6 days after administration of SK (P = 0.0004). Cultured T-cell lines showed similar proliferative responses to clinical-grade SK and recombinant SK. Marked differences in T-cell responses were apparent in response to each recombinant SK fragment (P = 0.04). The mean proliferative response exceeded background to only two peptides, peptide 2 (P = 0.04) and peptide 3 (P = 0.009). Peptide 3, representing amino acids 100-150 of mature SK, was recognized preferentially in the majority of assays. Marked variation in the T-cell response to SK following treatment with this agent was observed between subjects. Despite these differences, peptides 2 and 3 induced T-cell proliferation at a level significantly above background in the majority of subjects. These epitopes may represent a region of enhanced immunogenicity within SK.