When are pro-inflammatory cytokines SAFE in heart failure?

The cytokine hypothesis presently suggests that an excessive production of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF) and interleukin 6 (IL6), contributes to the pathogenesis of heart failure. The concept, successfully proved in genetically modified animal models, failed to translate to humans. Recently, accumulation of apparently paradoxical experimental data demonstrates that, under certain conditions, production of pro-inflammatory cytokines can initiate the activation of a pro-survival cardioprotective signalling pathway. This novel path that involves the activation of a transcription factor, signal transducer and activator of transcription 3 (STAT3), has been termed the survival activating factor enhancement (SAFE) pathway. In this review, we will discuss whether targeting the SAFE pathway may be considered as a preventive and/or therapeutic measure for the treatment of heart failur

Cardioprotective strategies are not “one size fi ts all”. Is it time to consider personalised medicine?

Since the discovery of the conditioning phenomenon in 1986 (whereby brief episodes of ischaemia reperfusion protect against a sustained ischaemic insult), thousands of preclinical studies have explored the benefits and signaling mechanisms of this cardioprotective strategy which aims to protect patients undergoing percutaneous coronary interventions (PCI), or cardiopulmonary bypass (CPB) surgery, against ischaemia reperfusion injury. A large number of proof of concept clinical trials have highlighted the benefits ofconditioning to protect patients against ischaemia reperfusion injury, but none have yet translated to the clinical routine. The outcomes of the multicenter studies ERICCA,(1) RIPHeart(2) and CIRCUS(3) which involved larger number of patients (1 612, 1 385 and 970 respectively) were eagerly awaited, hoping that pharmacological conditioning with cyclosporine A, or remote ischaemic preconditioning, could soon become part of the clinical routine

Influence of Tumour Necrosis Factor Alpha on the Outcome of Ischaemic Postconditioning in the Presence of Obesity and Diabetes

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC

Wine and heart health: learning from the French paradox

Wine with good food (albeit fatty) is an integral part of the French dietary pattern which is often called the French paradox. We note that among the inherent compounds in wine, especially red, that could confer cardioprotection, are resveratrol and melatonin. However, we do not think that drinking red wine is the sole explanation for the French paradox, whereby a rich high fat diet is associated with a lower than expected incidence of coronary heart disease. Rather, we note differences in French social behaviour – French eating is for refined pleasure and conviviality. ''Food is bought, cooked, and celebrated.'' Gardening with the availability and love of fresh vegetables is common. This lifestyle may be the key to the French paradox which, however, seems to be a passing phenomenon as dietary patterns and passion for gardening change even in France. Recent data suggest that, after all, the French are susceptible to the same rules as are other nations. The true Mediterranean diet pattern, found only in the relatively small geographic part of the South of France, is by contrast low in fat, with little red meat and rich in fish and olive oil. Like the French diet, it emphasises fresh fruit and vegetables and includes modest wine with the meals

Soluble ST2 correlates with some indicators of right ventricular function in hypertensive heart failure

Purpose: ST2 receptor, which is a member of the Toll-like/interleukin-1 (IL-1) receptor family, has been found to be increased in the serum of patients 1 day after myocardial infarction. Several other studies have shown that soluble ST2 levels correlate with severity of heart failure (HF), left ventricular ejection fraction, creatinine clearance, B-type natriuretic peptide and C-reactive protein, and are predictors of mortality in HF. Most of these studies were not only limited to ischemic heart disease but also concentrated on left-sided HF. We therefore decided to study the relationship between soluble ST2 and some markers of right ventricular (RV) function in a cohort of hypertensive HF subjects. Patients and methods: This is a prospective cohort study of hypertensive HF patients presenting to the University of Abuja Teaching Hospital, Abuja, over a 12-month period. ST2 was measured in plasma sample by the enzyme-linked immunosorbent assay (ELISA) method. Right ventricular diameters in diastole (RVDD) and right atrial area (RAA) were obtained on echocardiography, while right ventricular systolic pressure (RVSP) was estimated from echocardiography by the addition of the pressure gradient between the right ventricle and right atrium (RA) to the pressure in the RA. Results: There was a significant correlation between RVSP and soluble ST2 (t=0.75, p < 0.0001), RVDD (t=0.28, p=0.004) and RAA (t=0.46, p=0.002). Conclusion: In a cohort of hypertensive HF subjects, soluble ST2 correlates significantly with RVSP, RVDD and RAA

A comprehensive review: The evolution of animal models in pulmonary hypertension research; are we there yet?

Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans

Heart rate – a novel target for treatment of peripartum cardiomyopathy?

During pregnancy, heart rate (HR) is physiologically elevated but recovery occurs within 4 weeks of delivery.  Peripartum cardiomyopathy (PPCM) is an acute condition which manifests with symptoms of heart failure late during pregnancy, or within 6 months of delivery.  One of its main symptoms is elevated HR. Current standard therapy for PPCM makes use of diuretics, ACE inhibitors and beta-blockers. This approach does not satisfactorily improve HR in patients, even after 6 months of treatment. Strong evidence from both experimental and clinical studies suggests that modulation of the sino-atrial node with drugs such as ivabradine may benefi t patients suffering from PPCM.  The activity of ivabradine is likely two-fold – direct with regards to heart rate and indirect with long-term structural changes affecting the heart itself, as well as the vascular and endogenous physiological systems.  Large clinical trials are needed to validate this concept and further exploration of this hypothesis in an established rodent model of PPCM is required to investigate the outcome on both HR and its effects on other observable systems affected by PPCM