Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition.

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies.

The effects of short-term omission of daily medication on the pathophysiology of heart failure.

AIMS: Pharmacological therapies for heart failure (HF) aim to improve congestion, symptoms, and prognosis. Failing to take medication is a potential cause of worsening HF. Characterizing the effects of short-term medication omission could inform the development of better technologies and strategies to detect and interpret the reasons for worsening HF. We examined the effect of planned HF medication omission for 48 h on weight, echocardiograms, transthoracic bio-impedance, and plasma concentrations of NT-proBNP. METHODS AND RESULTS: Outpatients with stable HF and an LVEF <45% were assigned to take or omit their HF medication for 48 h in a randomized, crossover trial. Twenty patients (16 men, LVEF 32 ± 9%, median NT-proBNP 962 ng/L) were included. Compared with regular medication, omission led to an increase in NT-proBNP by 99% (from 962 to 1883 ng/L, P < 0.001), systolic blood pressure by 16% (from 131 to 152 mmHg, P < 0.001), and left atrial volume by 21% (from 69 to 80 mL, P = 0.001), and reductions in transthoracic bio-impedance by 10% (from 33 to 30 Σ, P = 0.001) and serum creatinine by 8% (from 135 to 118 µmol/L, P = 0.012). No significant changes in body weight, heart rate, or LVEF were observed. CONCLUSIONS: The characteristic pattern of response to short-term medication omission is of increasing congestion but, in contrast to the pattern reported for disease progression, with a rise in blood pressure and improved renal function. In stable HF, weight is not a sensitive marker of short-term diuretic omission.

Influence of case definition on incidence and outcome of acute coronary syndromes.

OBJECTIVE: Acute coronary syndromes (ACS) are common, but their incidence and outcome might depend greatly on how data are collected. We compared case ascertainment rates for ACS and myocardial infarction (MI) in a single institution using several different strategies. METHODS: The Hull and East Yorkshire Hospitals serve a population of ∼560 000. Patients admitted with ACS to cardiology or general medical wards were identified prospectively by trained nurses during 2005. Patients with a death or discharge code of MI were also identified by the hospital information department and, independently, from Myocardial Infarction National Audit Project (MINAP) records. The hospital laboratory identified all patients with an elevated serum troponin-T (TnT) by contemporary criteria (>0.03 µg/L in 2005). RESULTS: The prospective survey identified 1731 admissions (1439 patients) with ACS, including 764 admissions (704 patients) with MIs. The hospital information department reported only 552 admissions (544 patients) with MI and only 206 admissions (203 patients) were reported to the MINAP. Using all 3 strategies, 934 admissions (873 patients) for MI were identified, for which TnT was >1 µg/L in 443, 0.04-1.0 µg/L in 435, ≤0.03 µg/L in 19 and not recorded in 37. A further 823 patients had TnT >0.03 µg/L, but did not have ACS ascertained by any survey method. Of the 873 patients with MI, 146 (16.7%) died during admission and 218 (25.0%) by 1 year, but ranging from 9% for patients enrolled in the MINAP to 27% for those identified by the hospital information department. CONCLUSIONS: MINAP and hospital statistics grossly underestimated the incidence of MI managed by our hospital. The 1-year mortality was highly dependent on the method of ascertainment.

Development and course of heart failure after a myocardial infarction in younger and older people.

BACKGROUND: Acute myocardial infarction (AMI) is a common cause of heart failure (HF), which can develop soon after AMI and may persist or resolve or develop late. HF after an MI is a major source of mortality. The cumulative incidence, prevalence and resolution of HF after MI in different age groups are poorly described. This study describes the natural history of HF after AMI according to age. METHODS: Patients with AMI during 1998 were identified from hospital records. HF was defined as treatment of symptoms and signs of HF with loop diuretics and was considered to have resolved if loop diuretic therapy could be stopped without recurrence of symptoms. Patients were categorised into those aged < 65 years, 65-75 years, and > 75 years. RESULTS: Of 896 patients, 311, 297 and 288 were aged < 65, 65-75 and >75 years and of whom 24%, 57% and 82% had died respectively by December 2005. Of these deaths, 24 (8%), 68 (23%) and 107 (37%) occurred during the index admission, many associated with acute HF. A further 37 (12%), 63 (21%) and 82 (29%) developed HF that persisted until discharge, of whom 15, 44 and 62 subsequently died. After discharge, 53 (24%), 55 (40%) and 37 (47%) patients developed HF for the first time, of whom 26%, 62% and 76% subsequently died. Death was preceded by the development of HF in 35 (70%), 93 (91%) and 107 (85%) in aged < 65 years, 65-75 years and >75 years, respectively. CONCLUSIONS: The risk of developing HF and of dying after an MI increases progressively with age. Regardless of age, most deaths after a MI are preceded by the development of HF.

Construction of eukaryotic expression vectors encoding CFP-10 and ESAT-6 genes and their potential in lymphocyte proliferation.

BACKGROUND: Mycobacterium (M.) bovis is the agent of bovine tuberculosis (TB) in a range of animal species, including humans. Recent advances in immunology and the molecular biology of Mycobacterium have allowed identification of a large number of antigens with the potential for the development of a new TB vaccine. The ESAT-6 and CFP-10 proteins of M. bovis are important structural and functional proteins known to be important immunogens. METHODS: In the current study, the DNAs encoding these genes were utilized in the construction of pcDNA 3.1+/ESAT-6 and pcDNA3.1+/CFP-10 plasmids. After intramuscular injection of BALB/c mice with these plasmids, ESAT-6 and CFP-10 mRNA expression was assessed by RT-PCR. Mice were inoculated and boosted with the plasmids to evaluate their effects on lymphocyte proliferation. RESULTS: Our results indicate the plasmids are expressed at the RNA level and can induce lymphocyte proliferation. CONCLUSION: Further study is needed to characterize the effect of these antigens on the immune system and determine whether they are effective vaccine candidates against M. bovis.

Quantiation of IL-4, IL-10 and IFN-γ genes expression after immunization of mice with CFP-10 and ESAT-6 containing vectors.

BACKGROUND: Tuberculosis is a disease with high morbidity, caused mainly by Mycobaterium tuberculosis (M.tb.). DNA vaccines show a promising future due to their unique advantages over conventional methods. The early-secreted antigen target (ESAT)-6 and culture filtrate protein (CFP)-10 of M.tb. antigens have been identified as vaccine candidates against Mycobacteria and used as subunit vaccines, DNA or protein, in different studies. OBJECTIVE: To investigate the potential of pcDNA3.1+ plasmid containing CFP-10 and ESAT-6 genes in induction of local immune responses after intramuscular injection in BALB/c mice. METHODS: pcDNA 3.1+ CFP-10 and pcDNA3.1+ ESAT-6 plasmids were prepared and defined groups of mice were injected intramuscularly with the plasmids both separately and in combination. The RNA was extracted from muscles after one month and cDNA was made using RT-PCR. The expressions of IL-4, IL-10 and IFN-γ genes cytokines were evaluated using comparative real time PCR. RESULTS: Expression of IL-4 and IL-10 increased in the injection site of the mice groups which received plasmids encoding ESAT-6 and CFP-10 individually or together. More than 10-fold increase in IFN-γ expression was found in samples taken from mice groups inoculated by plasmids encoding ESAT-6 and CFP-10 individually or together. CONCLUSION: pcDNA 3.1+ESAT-6 and pcDNA3.1+CFP-10 plasmids can increase the expression of IFN-γ in mice after immunization.

Clinical trials update from the European Society of Cardiology Meeting 2010: SHIFT, PEARL-HF, STAR-heart, and HEBE-III.

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the annual meeting of the European Society of Cardiology held in Stockholm in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The SHIFT study supports the use of ivabradine in patients with HF due to left ventricular systolic dysfunction and resting sinus rhythm rate ≥70 b.p.m. despite treatment with beta-blockers or where beta-blockers are contra-indicated. Results from PEARL-HF suggest that the potassium binding polymer RLY5016 may be useful for both prevention and treatment of hyperkalaemia in HF patients with or without concomitant chronic kidney disease. The STAR-heart study provides encouraging observational data about the potential for intracoronary stem cell transplantation in patients with HF. Results from HEBE-III showed no effect of erythropoietin on ejection fraction measured 6 weeks post-MI; although there were fewer cardiovascular events in patients assigned to erythropoietin, the study was too small to provide conclusive evidence of effect.

Clinical trials update from the European Society of Cardiology Heart Failure meeting 2009: CHANCE, B-Convinced, CHAT, CIBIS-ELD, and Signal-HF.

This paper provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the Heart Failure Association of the European Society of Cardiology held in Nice. The CHANCE study showed a substantial reduction in morbidity and mortality in a randomized controlled trial (RCT) of a multidisciplinary management programme for patients with chronic heart failure in Russia. Data from the B-Convinced study, also an RCT, suggest that continuation of beta-blocker (BB) therapy in patients hospitalized with worsening heart failure may be associated with improved outcomes when compared with treatment discontinuation. The CHAT study suggests that telephone support can improve prognosis in heart failure patients living in remote rural locations. CIBIS-ELD showed that titration of BBs to target doses in older patients with heart failure is more difficult; but tolerance levels were similar for bisoprolol and carvedilol. Signal-HF randomized elderly heart failure patients to treatment guided by NT-proBNP levels or usual care, and showed no effect of NT-proBNP-guided treatment on outcomes.

Clinical trials update from the European Society of Cardiology Meeting 2009: AAA, RELY, PROTECT, ACTIVE-I, European CRT survey, German pre-SCD II registry, and MADIT-CRT.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the European Society of Cardiology held in Barcelona in 2009. The AAA study does not support the routine use of aspirin for the prevention of vascular events in patients with asymptomatic atherosclerosis. RELY suggests that dabigatran may be more effective than warfarin for the prevention of stroke in patients with atrial fibrillation. Rolofylline was not superior to placebo in improving outcomes in patients with acute heart failure enrolled in the PROTECT study, but dyspnoea was improved. Data from ACTIVE-I suggest that irbesartan does not provide additional therapeutic benefit in patients with atrial fibrillation who are well controlled on current therapy. The European cardiac resynchronization therapy (CRT) survey provides interesting epidemiological data on current CRT device usage. The German pre-SCD II registry identified a low prevalence of patients with a reduced ejection fraction following myocardial infarction. Implantation of CRT-D rather than an implantable cardioverter defibrillator in patients with mild heart failure and QRS >/=130 ms reduced the risk of hospitalization for heart failure in MADIT-CRT; mortality was similarly low with each device.

The timing of development and subsequent clinical course of heart failure after a myocardial infarction.

AIMS: Myocardial infarction (MI) is a common cause of heart failure (HF), which may develop early and persist or resolve, or develop late. The cumulative incidence, persistence, and resolution of HF after MI are poorly described. The aim of this study is to describe the natural history and prognosis of HF after an MI. METHODS AND RESULTS: Patients with a death or discharge diagnosis of MI in 1998 were identified from records of hospitals providing services to a local community of 600 000 people. Records were scrutinized to identify the development of HF, defined as signs and symptoms consistent with that diagnosis and treated with loop diuretics. HF was considered to have resolved if diuretics could be stopped without recurrent symptoms. Totally, 896 patients were identified of whom 54% had died by December 2005. During the index admission, 199 (22.2%) patients died, many with HF, and a further 182 (20.3%) patients developed HF that persisted until discharge, of whom 121 died subsequent to discharge. Of 74 patients with transient HF that resolved before discharge, 41 had recurrent HF and 38 died during follow-up. After discharge, 145 (33%) patients developed HF for the first time, of whom 76 died during follow-up. Overall, of 281 deaths occurring after discharge, 235 (83.6%) were amongst inpatients who first developed HF. CONCLUSION: The development of HF precedes death in most patients who die in the short- or long-term following an MI. Prevention of HF, predominantly by reducing the extent of myocardial damage and recurrent MI, and subsequent management could have a substantial impact on prognosis.