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Despite current treatment options, the clinical course of patients with chronic heart failure is notoriously difficult to predict. Among those with similar etiologies, ejection fractions, and patient demographics, our understanding of why such variations in outcomes exist remains limited. Evidence that has been progressively gathered implicates an important role of the immune system in the propagation of heart failure. This has been derived mainly from observations that cytokines are progressively elevated in patients with poor outcomes. However, attempts at introducing various immunomodulatory therapies as a new treatment strategy have been largely unsuccessful to date. This possibly reflects a failure in recognizing the complexity of the immune system's role in chronic heart failure, which has led to an oversimplified approach to treatment. This review critically analyzes the immune treatments attempted to date and hypothesizes what is required to develop a successful future treatment strategy.

HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, or 'statins', have revolutionized the management of patients with atherosclerotic vascular disease. Following 2 large acute coronary syndrome trials, additional clinical benefit outside their effect of low-density lipoprotein (LDL) lowering was proposed. This concept was introduced following the observation of cardiovascular event rate reduction, only weeks after initiation of treatment and supposedly before the effect of LDL lowering could have influenced atheroma volume burden. Furthermore, there has been a substantial compilation of experimental data demonstrating beneficial effects of statins on inflammation, thrombosis, platelet aggregation, immunomodulation and endothelial function. These are hypothesized to occur via the interruption of the mevalonate pathway. However, the absolute benefit of these non-lipid-lowering effects, often referred to as 'pleiotropic effects', has been challenged by meta-analysis data. Anti-inflammatory actions have also been proposed to occur by the process of LDL lowering alone rather than due to a unique property of statins. Furthermore, some experimental data reports have shown evidence of pleiotropic effects in non-statin lipid-modifying agents. In this review article, we consolidate what is known so far and critically analyse the literature in order to highlight the outstanding issues., (Copyright 2008 S. Karger AG, Basel.)

Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.

Use of C(2) monitoring for cyclosporine A (CsA) microemulsion results in improved clinical outcomes vs. trough (C(0)) monitoring. Logistical issues include accurate timing of the C(2) sample; requirement for sample dilution with most standard assay techniques; and inconvenience for patients. Recently, it has been shown that CsA concentrations in capillary blood correlate closely with levels in venepuncture samples, and that liquid chromatography tandem mass spectrometry (LC-MS/MS) can analyse CsA concentration using undiluted capillary blood from fingerprick samples. In a study to assess the feasibility of CsA monitoring, 52 stable heart transplant patients were provided with kits to take fingerprick trough and C(2) blood samples at home, returning them to the laboratory by post for LC-MS/MS analysis. In total, 225 samples were provided, of which 14 (6%) were unsuitable for analysis because of clotting (n = 10) or insufficient volume (n = 4). Discomfort was not a problem and initial difficulties that some patients reported in taking the samples resolved with experience. All samples were returned by the postal system in a timely manner. Use of fingerprick assays could allow transplant physicians to have access to C(2) levels when patients visit the clinic for review, and avoids the need for patients to attend the clinic or local healthcare centre solely for venepuncture. A barrier to more widespread introduction of fingerprick testing is likely to be lack of suitable MS facilities and trained personnel. In conclusion, self-administered fingerprick testing for CsA blood levels is practical to implement and highly convenient for patients and offers advantages for the transplant team.

Background: The development of coronary vasculopathy (CV) limits survival after cardiac transplantation. Interferon (IFN)-gamma is an important immunomodulator affecting the growth and function of T cells and macrophages, free radical formation, adhesion molecule, and MHC class I and II expression, which are important processes for CV formation. IFN-gamma is expressed early after transplantation and neutralization or genetic absence of the cytokine can abrogate CV development. The expression of IFN-gamma is influenced by a dinucleotide repeat in the first intron of the IFN-gamma gene. We investigated the effect of this polymorphism on the development of CV., Methods: Using sequence specific primers to the IFN-gamma polymorphic region, polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 144 cardiac transplant recipients and 134 donors. An association was sought between the presence of a high, intermediate or low IFN-gamma producing genotype and the development of CV diagnosed by routine surveillance posttransplant angiography., Results: High, intermediate, and low IFN-gamma producers made up 29.2%, 44.4%, 26.4% and 24.6%, 40.3%, 35.1% of recipients and donors respectively (p = NS). IFN-gamma polymorphism in cardiac graft recipients had no impact on the time to first diagnosis of CV; high producers 4.03 years (+/- 129.9 days), intermediate producers 3.40 years (+/- 79.7 days), low producers 4.01 years (+/- 102.9 days); p = 0.16. Similar results were found on investigating donor polymorphism; high producers (3.68 years +/- 120.1 days), intermediate producers (3.83 years +/- 105.9 days), low producers (3.3 years +/- 77.7 days); p = 0.35. Multivariate analysis identified the number of rejection episodes of ISHLT grade 3 or greater and increasing donor age to be independent risk factors for CV development., Conclusions: Dinucleotide repeat polymorphism in the first intron of the human IFN-gamma gene does not influence CV development and cannot be used as a genetic risk marker.