Steven M Shaw

Neuroendocrine Effects on the Heart and Targets for Therapeutic Manipulation in Heart Failure

Chronic heart failure (CHF) involves derangements in multiple neurohormonal axes leading to a procatabolic state and wasting syndrome associated with significant mortality. Catabolic abnormalities include excess catecholamines and glucocorticoids. Anabolic defects include deficiencies of sex steroids, insulin resistance, and growth hormone (GH) resistance. These abnormalities are also correlated with increased morbidity and mortality in CHF. Anabolic axes have been augmented in pilot studies in CHF with testosterone, GH, insulin-like growth factor-1, and GH secretagogues. Results have been varied although some treatments have been associated with improved surrogate endpoints. This review article explores the current understanding of metabolic derangements in CHF and highlights potential neuroendocrine treatment strategies.

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.

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.

Review article: Thiazolidinediones and heart failure

DM is an independent risk factor for the development of HF and its presence confers an adverse prognosis for those already diagnosed with HF.TZDs are potent insulin-sensitisers associated with a number of beneficial cardiovascular effects. However,TZDs increase renal sodium and water reabsorption, leading to fluid retention and overt signs of HF in patients with diabetes. Rosiglitazone has also been associated with an increased risk of myocardial infarction and cardiovascular mortality. However, pioglitazone may have macrovascular benefits. The majority of data on the cardiovascular safety of TZDs are based on non-cardovascular outcome trials and meta-analyses. Concerns regarding the risk of HF and cardiovascular safety of TZDs have led to restrictions on their use in patients with HF. This review addresses the latest evidence for HF with each of the TZD drugs currently available and reflects on the current guidelines regarding their prescription in at-risk patients.

Effect of antipsychotic medications on glucose and lipid levels

Severe mental illnesses, such as schizophrenia and bipolar affective disorder, are associated with excess cardiovascular morbidity and mortality. Cardiovascular risk in psychiatric disorders is partly related to antipsychotic therapy, especially second‐generation or atypical antipsychotics. Some antipsychotic medications are associated with proatherogenic conditions including insulin resistance and dyslipidemia. In particular, olanzapine and clozapine have been consistently demonstrated to promote insulin resistance and dyslipidemia. Ziprasidone and amisulpiride may be associated with more favorable metabolic effects. Many of the published data relating to metabolic effects of antipsychotics originate from retrospective studies. However, prospective randomized‐controlled data are emerging, and the latest evidence is described here.

The efficacy and tolerability of ezetimibe in cardiac transplant recipients taking cyclosporin.

Background. Despite statin treatment, hyperlipidemia remains problematic after cardiac transplantation and is associated with the development of cardiac allograft vasculopathy. The cholesterol absorption inhibitor ezetimibe may offer a viable option for add on therapy; however, questions have been raised regarding the safety of this during concomitant cyclosporin treatment. Methods. This is the first placebo controlled, randomized double blinded trial assessing the efficacy and tolerability of ezetimibe in cardiac transplant recipients receiving cyclosporin. Sixty-eight cardiac transplant patients were randomized to receive ezetimibe (10 mg) or matching placebo for 6 months in addition to usual treatments. Fasting blood tests were performed at regular time intervals during the study. Results. Fifty-nine patients completed the study. At 6 months, ezetimibe had reduced total cholesterol by 18% (5.4±1.1 to 4.4±0.7 mmol/L, P<0.001), low-density lipoprotein cholesterol by 26% (3.0±1.0 to 2.1±0.7 mmol/L, P<0.001), and triglycerides by 13.5% (2.3±1.3 to 1.8±0.9 mmol/L, P=0.02). Tolerability was excellent with no patients experiencing predefined safety endpoints. An equal number of patients withdrew consent from each arm of the study because of perceived side effects. Specific analysis confirmed ezetimibe had no significant effect on cyclosporin levels. Conclusion. We conclude that ezetimibe is both efficacious and tolerable in cardiac transplant recipients taking cyclosporin. It can be safely considered as add on therapy in patients taking statins (or as monotherapy) to further reduce low-density lipoprotein levels, which may in turn reduce the risk of cardiac allograft vasculopathy.

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

BACKGROUND The 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. METHODS PBMCs 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. RESULTS BNP 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). DISCUSSION BNP 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.

Does brain natriuretic peptide interact with the immune system after cardiac transplantation

Brain natriuretic peptide (BNP) is a marker of diagnosis and prognosis in patients with chronic heart failure. Stored in ventricular myocytes, it is released during ventricular stretch and increased transmural pressure. However, BNP behaves unusually after cardiac transplantation, with a failure to return to normal levels. This raises a question over whether other processes are involved in both its production and secretion. Several studies suggest BNP levels are associated with allograft rejection and coronary graft vasculopathy. Both of these processes have a single denominator in common, the activated immune system. This overview considers further evidence suggesting that BNP interacts with the immune system after cardiac transplantation.