Simon G. Williams

The Immune System and Chronic Heart Failure : Is the Heart in Control?

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 systems 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.

Pleiotropic effects and cholesterol-lowering therapy.

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.

The development of left ventricular torsion and its clinical relevance.

Left ventricular torsion is a measurement derived from the twisting or wringing motion of the heart around its long axis. The calculation is made by measuring the magnitude of rotation at the apex of the heart, and subtracting the rotation at the base. Although the phenomenon of left ventricular twisting was first described in the 17th Century, it wasnt until the 1960s that the first invasive method of measurement was demonstrated. Silver tantalum clips were sutured into the epicardium during cardiac surgery and viewed using cineradiography. Non-invasive torsion measurement has been subsequently developed, adopting Magnetic Resonance Imaging and 2D echocardiography. Interest in the changes of different components of torsion, during various cardiac disease states has developed with the advent of these non-invasive measurement techniques. This review article summarises the history of the development of torsion analysis and describes the known changes of torsion during different clinical circumstances.

Immunological mechanisms of pentoxifylline in chronic heart failure

The progressive syndrome of chronic heart failure (CHF) represents a common disease pathway that may be derived from a host of varying insults (including myocardial ischaemia and infarction, hypertension, viral infection, pregnancy, etc). Despite this multifarious aetiology, a common phenomena observed in CHF patients is elevated levels of tumour necrosis factor (TNF)‐α. This has led to the widespread concept that TNF‐α is directly involved in the pathophysiology of CHF and as such, attempts have been made to inhibit TNF‐α production in this cohort. However, to date, there have been no clear beneficial effects from TNF‐α inhibition and indeed trials of direct anti‐TNF therapy have provoked worsening of clinical outcomes. Conversely, a possible exception is pentoxifylline (PTX), a putative TNF‐α inhibitor with possible (but ill‐defined) vasodilatory properties. Several small clinical trials assessing the use of PTX in CHF have suggested beneficial effects on multiple surrogate clinical markers. Interestingly, these trials failed to show a concordant effect on circulating TNF despite the clinical improvement, suggesting other key beneficial properties of this novel agent. This review article provides an insight into the potential beneficial mode of the action of PTX in CHF and calls for more investigation of this interesting agent.

Mannose-binding Lectin Deficiency Offers Protection From Acute Graft Rejection After Heart Transplantation

Mannose-binding lectin (MBL) deficiency (or the common opsonic defect) has been reported as a risk factor for several immunologically controlled conditions, including infection and graft rejection. However, the effects of MBL deficiency on acute rejection after heart transplantation are unknown. Ninety heart transplant recipients were included in this study. Plasma MBL quantification was performed using a commercially available enzyme-linked immunoassay (ELISA). Acute rejection was diagnosed via endomyocardial biopsy and histologic assessment. MBL concentration was controlled for demographics, immunosuppression and anti-viral therapy. Individuals with dysfunctional MBL had significantly fewer rejection episodes (6.3 +/- 3.8%) than those with functional MBL (12.9 +/- 11.6%) (p = 0.016). We found no significant difference between MBL concentrations among those with (1,232 +/- 58 ng/ml) and those without (1,216 +/- 161 ng/ml) GCAD (p = 0.841). There was also no significant difference between the incidence of GCAD in those with normal concentrations (p = 0.782). Heart transplant recipients with MBL deficiency had fewer acute graft rejection episodes compared to patients with functional MBL. This suggests the lectin pathway of complement activation is an important process in graft rejection. Furthermore, functional MBL may indicate a greater likelihood of rejection.

Decreased immune responses to influenza vaccination in patients with heart failure.

BACKGROUNDnHeart failure (HF) patients are at risk for influenza despite widespread vaccination. Both humoral (antibody) and cytotoxic T-lymphocyte (CTL) responses are important for protection. We explored antibody- and CTL-mediated responses to the influenza vaccine in HF patients compared with healthy controls.nnnMETHODS AND RESULTSnWe studied 29 HF patients (9 ischemic, 20 nonischemic) stable on HF therapies and 17 healthy controls. Participants had phlebotomy before and after influenza vaccination. Antibody production was measured in serum by hemagglutination inhibition assay and CTL responses (via interferon [IFN]-gamma and interleukin [IL]-10 production) were measured in isolated peripheral blood mononuclear cells with enzyme-linked immunosorbent assay. CTL responses demonstrated increased IL-10 production in HF patients after vaccination (P = .002), but similar IFN-gamma responses to healthy controls. All participants demonstrated antibody seroprotection; groups had similar rates of seroconversion (P = NS). Antibody-mediated response to the newest vaccine antigen, H3N2, was reduced in HF (P = .009).nnnCONCLUSIONSnPatients with HF had higher vaccine induced IL-10 concentrations, suggesting a different CTL phenotype for vaccine responses. HF patients did not mount as vigorous of an antibody immune response to the newest vaccine viral strain compared with healthy individuals. These data suggest that immunologic memory may be important for vaccine protection in HF patients.

HMG-CoA reductase inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation

BACKGROUNDnMonocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage/dendritic cell lineages. To date, the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated. This study was designed to assess the effects of statin administration on the monocyte repertoire.nnnMETHODSn108 patients were recruited into the study. Clinical data were collected from patients notes. Peripheral blood immunophenotype was determined via flow cytometry (using CD11c, CD14, CD16, CD49d, CD64, CD80 and CD195).nnnRESULTSnThere were fewer circulating classical (p=0.0001) and non-classical (p=0.0013) monocytes in patients treated with a statin. CD64 expression was down-regulated (p=0.011 and p=0.049) whereas CD49d expression was up-regulated (p=0.004 and p=0.022) on classical and non-classical monocytes in this group. Patients receiving Atorvastatin had fewer circulating classical monocytes (p=0.001) compared to patients administered Pravastatin. Patients receiving Pravastatin had fewer circulating non-classical monocytes (p=0.029) compared to patients administered Atorvastatin.nnnDISCUSSIONnStatin administration alters the circulating monocyte repertoire following heart transplantation, including population size, FcgammaRI and VLA-4 adhesion molecule expression. Furthermore, different statin treatments are associated with a selective depletion of macrophage or DC (re)generating monocytes.

Biological Phenotypes of Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, which result in the heterogeneous phenotypes that are evident clinically, and which have potentially confounded previous HFpEF trials. A greater understanding of the inxa0vivo human processes involved, and in particular, which are the causes and which are the downstream effects, may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on the underlying biology. From this, specific interventions can follow, targeting individuals identified on the basis of their biological phenotype. This review describes the biological phenotypes of HFpEF and therapeutic interventions aimed at targeting these phenotypes.

The Pathophysiology of Chronic Graft Failure in the Cardiac Transplant Patient

Following cardiac transplantation, many patients develop chronic deterioration of graft function, which may lead to a clinical syndrome similar to native chronic heart failure (CHF). This condition of chronic cardiac graft failure (CGF) may also share pathophysiological processes comparable with that of CHF. However, the unique environment following cardiac transplantation may also contribute with a variety of unique mechanisms, deserved of special attention. This review article discusses the complex pathophysiology of CGF after cardiac transplantation, an important yet neglected condition of transplant medicine.

BNP directly immunoregulates the innate immune system of cardiac transplant recipients in vitro

BACKGROUNDnThe innate immune system plays an important role in cardiac allograft rejection. BNP has frequently been reported to elevate during acute cardiac rejection, yet the explanation behind this phenomenon is unclear. We hypothesized that BNP might interact with the innate immune system in cardiac transplant recipients and devised a series of in vitro culture experiments to explore this phenomena.nnnMETHODSnPBMCs were isolated from whole blood of (total n = 40) cardiac transplant recipients. Short (24h, n = 20) and long term (72h, n = 20) co-cultures of innate cells in the presence or absence of BNP were performed. BNP was added at two specific concentrations and compared to placebo control. Innate cells were immunophenotyped using flow cytometry.nnnRESULTSnBNP dose dependently reduced the total number of monocytes, B cells and NK cells. Furthermore, BNP co-culture impaired NK cell cytotoxicity and adhesion of non-classical monocytes (via down-regulation of CD11c).nnnDISCUSSIONnBNP has an additional physiological role of moderating components of the innate immune system. Although speculative, this could be beneficial to cardiac transplant recipients as the innate immune system is involved in allograft rejection. Further investigation is required to elucidate the mechanism behind how BNP affects immune cells and whether the same effects are consistent with the adaptive immune system.