CT coronary angiography-guided cardiovascular risk screening in asymptomatic patients: is it time?

Cardiovascular disease (CVD) is the leading cause of death in the UK, whilst millions live with various forms of the disease. Coronary artery disease constitutes a significant portion of this morbidity and mortality, and is the leading cause of premature death. Increasing focus is thus being placed on the optimisation of CVD prevention, where risk screening plays a key role. Indeed, the decline in age-adjusted cardiovascular mortality achieved up to now has been largely attributed to primary preventative therapies (e.g., statins) introduced earlier in the disease process. National initiatives exist to improve cardiovascular health at a population level, but in its current form, CVD screening at the individual level is predominantly undertaken using multivariate risk scores based on population-based data. These have multiple innate flaws, highlighted in this review. Non-invasive imaging plays a key role in the screening of other disease processes, helping to personalise the screening process. Although the coronary artery calcium score as a screening tool has a role in national and international guidance, whether a shift to screening with computed tomography coronary angiography (CTCA) is now appropriate is open for discussion. Image acquisition techniques continue to improve with reducing radiation exposure and an ever-expanding evidence-base for additional prognostic data offered by CTCA. This enables the potential identification of sub-clinical atherosclerosis, including with novel artificial intelligence techniques. This review aims to report current guidelines regarding cardiac CT imaging in the asymptomatic primary prevention setting, advances in various CT technologies and future opportunities for progress in this field.

Effect of glycaemic control on complications following cardiac surgery: literature review.

INTRODUCTION: No uniform consensus in the UK or Europe exists, for glycaemic management of patients with Diabetes or pre-diabetes undergoing cardiac surgery. OBJECTIVE: [i] Determine the relationship between glycaemic control and cardiac surgical outcomes; [ii] Compare current vs gold standard management of patients with Diabetes or pre-diabetes undergoing cardiac surgery. METHODS: Searches of MEDLINE, NHS Evidence and Web of Science databases were completed. Articles were limited to those in English, German and French. No date limit was enforced.13,232 articles were identified on initial literature review, and 50 relevant papers included in this review. RESULTS: No national standards for glycaemic control prior to cardiac surgery were identified. Upto 30% of cardiac surgical patients have undiagnosed Diabetes. Cardiac surgical patients without Diabetes with pre-operative hyperglycaemia have a 1 year mortality double that of patients with normoglyacemia, and equivalent to patients already diagnosed with Diabetes. Pre- and peri-operative hyperglycaemia is associated with worse outcomes. Evidence regarding tight glycaemic control vs moderate glycaemic control is conflicting. Tight control may be more effective in patients without Diabetes with pre-/peri-operative hyperglycaemia, and moderate control appears more effective in patients with pre-existing Diabetes. Patients with well controlled Diabetes may achieve comparable outcomes to patients without Diabetes with similar glycaemic control. CONCLUSIONS: Pre / peri-operative hyperglycaemia is associated with worse outcomes in both patients with, and without Diabetes undergoing CABG. This review supports the pre-operative screening, and optimisation of glycaemic control in patients undergoing cardiac surgery. Optimal glycaemic management remains unclear and clear guidelines are needed.

The Cognitive Role of the Globus Pallidus interna; Insights from Disease States.

The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.

From the BMI paradox to the obesity paradox: the obesity-mortality association in coronary heart disease.

Despite a strong association between body weight and mortality in the general population, clinical evidence suggests better clinical outcome of overweight or obese individuals with established coronary heart disease. This finding has been termed the 'obesity paradox', but its existence remains a point of debate, because it is mostly observed when body mass index (BMI) is used to define obesity. Inherent limitations of BMI as an index of adiposity, as well as methodological biases and the presence of confounding factors, may account for the observed findings of clinical studies. In this review, our aim is to present the data that support the presence of a BMI paradox in coronary heart disease and then explore whether next to a BMI paradox a true obesity paradox exists as well. We conclude by attempting to link the obesity paradox notion to available translational research data supporting a 'healthy', protective adipose tissue phenotype. © 2016 World Obesity.

TAM receptor tyrosine kinase function and the immunopathology of liver disease.

Tyro3, Axl, MERTK (TAM) receptor tyrosine kinases are implicated in the regulation of the innate immune response through clearance of apoptotic cellular debris and control of cytokine signaling cascades. As a result they are pivotal in regulating the inflammatory response to tissue injury. Within the liver, immune regulatory signaling is employed to prevent the overactivation of innate immunity in response to continual antigenic challenge from the gastrointestinal tract. In this review we appraise current understanding of the role of TAM receptor function in the regulation of both innate and adaptive immunity, with a focus on its impact upon hepatic inflammatory pathology.

Differences in arterial stiffness and target organ damage between native Greek patients and immigrants from Eastern European countries with essential hypertension.

AIM: The variance in hypertension-related sequelae between different ethnic groups is highly related to differences in socioeconomic conditions and lifestyle habits, but also to disparities in the awareness and treatment of the disease. In the present study, we sought to evaluate the target organ damage in a vulnerable hypertensive population, such as the Eastern European immigrants. METHODS: The study population consisted of 128 hypertensive patients: 67 immigrants from Eastern Europe and 61 native inhabitants. Anthropometric, biochemical and echocardiographic data were derived from both groups. Both groups underwent fundoscopic examination and pulse wave velocity (PWV) measurements for assessment of arterial stiffness. RESULTS: Although immigrants had lower body mass index compared to native inhabitants (P<0.001), they had significantly increased arterial stiffness (P=0.003). In multivariate analysis, higher carotid-femoral PWV was significantly associated with immigration status [ß (SE)=0.935(0.443), P=0.041], after adjustment for smoking status. Moreover, immigrants had increased left atrial volume index (LAVI) (P<0.001), left ventricular mass index (P<0.001) and higher rates of left ventricular diastolic dysfunction (p=0.047). In multivariate analysis, LAVI was significantly associated with immigration status (ß (SE)=5.17(1.93), P=0.01) after adjustment for serum glucose levels and age. Finally, immigrants had significantly higher levels of sodium urinary excretion (p=0.007) and lower glomerular filtration rate (P<0.001). CONCLUSION: Our findings suggest that hypertensive immigrants exhibit an aggravated arterial stiffness profile and increased risk of target organ damage. These findings could be attributed to differences in socioeconomic conditions and dietary habits.

Ocular motor abnormalities in neurodegenerative disorders.

Eye movements are a source of valuable information to both clinicians and scientists as abnormalities of them frequently act as clues to the localization of a disease process. Classically, they are divided into two main types: those that hold the gaze, keeping images steady on the retina (vestibulo-ocular and optokinetic reflexes) and those that shift gaze and redirect the line of sight to a new object of interest (saccades, vergence, and smooth pursuit). Here we will review some of the major ocular motor abnormalities present in neurodegenerative disorders.

Wnt signaling in cardiovascular physiology.

Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis.

Assessment of acute coronary syndromes: focus on novel biomarkers.

Coronary artery disease (CAD) is the leading cause of mortality in Western Societies and several developing countries. Recent evidence suggests that most detrimental clinical manifestations of CAD, such as acute coronary syndromes (ACS), are the outcome of inflammatory processes that lead to plaque formation and rupture and eventually to ischemia and potentially myocardial necrosis. Neither of the traditionally used biomarkers is thought to be the gold standard in detection of myocardial ischemia or necrosis. A biomarker that could detect quite early the ischemic myocardium as well as define the risk of a future event with high sensitivity and specificity is still lacking. Several biomarkers, implicated in the pathogenesis and clinical evolution of atherosclerosis, have emerged as potent biomarkers for early detection of myocardial ischemia. In the current review, we summarize recent evidence of the most promising biomarkers and discuss their potential role in clinical practice in patients suffering from ACSs.

Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations.

Oxidative stress is a key feature in atherogenesis, since reactive oxygen species (ROS) are involved in all stages of the disease, from endothelial dysfunction to atheromatic plaque formation and rupture. It is therefore important to identify reliable biomarkers allowing us to monitor vascular oxidative stress status. These may lead to improved understanding of disease pathogenesis and development of new therapeutic strategies. Measurement of circulating biomarkers of oxidative stress is challenging, since circulation usually behaves as a separate compartment to the individual structures of the vascular wall. However, measurement of stable products released by the reaction of ROS and vascular/circulating molecular structures is a particularly popular approach. Serum lipid hydroperoxides, plasma malondialdehyde or urine F2-isoprostanes are widely used and have a prognostic value in cardiovascular disease. Quantification of oxidative stress at a tissue level is much more accurate. Various chemiluminescence and high performance liquid chromatography assays have been developed over the last few years, and some of them are extremely accurate and specific. Electron spin resonance spectroscopy and micro-electrode assays able to detect ROS directly are also widely used. In conclusion, measurement of circulating biomarkers of oxidative stress is valuable, and some of them appear to have predictive value in cardiovascular disease. However, these biomarkers do not necessarily reflect intravascular oxidative stress and therefore cannot be used as therapeutic targets or markers to monitor pharmacological treatments in clinical settings. Measurement of vascular oxidative stress status is still the only reliable way to evaluate the involvement of oxidative stress in atherogenesis.

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.

Endothelin-1 increases superoxide production in human coronary artery bypass grafts.

AIMS: Endothelin-1 (ET-1) has been shown to increase endothelial superoxide (O(2)(-)) production in experimental animal models. It is unclear whether ET-1 increases O(2)(-) production in humans. We sought to elucidate whether ET-1 increases O(2)(-) production in human vessels and to identify the mechanism behind this effect. MAIN METHODS: Segments of internal mammary artery (IMA) and human saphenous vein (HSV) were harvested from 90 patients undergoing elective coronary artery bypass graft surgery. Paired vessel rings were incubated in the presence and absence of ET-1 (10(-10)M), the ET(A) receptor antagonist BQ123 alone, or in combination with the ET(B) receptor antagonist BQ788 (dual BQ) and known inhibitors of sources of O(2)(-) and further analysed for O(2)(-) production using lucigenin-enhanced chemiluminescence and DHE fluorescence. KEY FINDINGS: ET-1 increased O(2)(-) production in both IMA (2.6 ± 1.5 vs. 1.4 ± 0.8 relative light units/s/mg tissue (RLU); n=33; p < 0.0001) and HSV (1.4 ± 0.8 vs. 1.1 ± 0.6 RLU; n=24; p<0.05). The increase in O(2)(-)production induced by ET-1 in IMA was inhibited by co-incubation with dual BQ (p < 0.05; n=15) and BQ123 (p<0.05; n = 17). Of known O(2)(-) inhibitors, only incubation with Tiron and diphenyleneiodonium resulted in a significant reduction in ET-mediated O(2)(-) production. SIGNIFICANCE: ET-1 increases O(2)(-) production especially in human arteries and less so in veins from patients with coronary artery disease via a receptor-dependent pathway involving a flavin dependent enzyme which is likely to be NADPH oxidase. Production of O(2)(-) may be an important factor underlying the negative effects of ET-1 on vascular function such as impairment of endothelium-dependent vasodilatation and pro-inflammatory effects.

Effects of atorvastatin on endothelial function and the expression of proinflammatory cytokines and adhesion molecules in young subjects with successfully repaired coarctation of aorta.

OBJECTIVE: To investigate the effects of atorvastatin on endothelial function and low-grade systemic inflammation in subjects with successful surgery for aortic coarctation repair (SCR). DESIGN: Open-label study. SETTING: Outpatients visiting the adult congenital heart disease department of our hospital. PATIENTS: 34 young people with SCR. INTERVENTIONS: Patients with SCR received atorvastatin 10 mg/day (n=17) or no treatment (n=17) for 4 weeks. At baseline and at 4 weeks, endothelial function was assessed by flow-mediated dilatation (FMD) of the right brachial artery, and blood samples were obtained. Serum levels of interleukin (IL) 1b, IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISA. MAIN OUTCOME MEASURES: Effects of treatment on FMD and serum levels of IL-1b, IL-6 and sVCAM-1. RESULTS: FMD in the atorvastatin group was significantly improved after 4 weeks (from 6.46±0.95% to 11.24±1.38%, p<0.01), while remaining unchanged in the control group (from 6.74±0.58% to 6.95±0.53%, p=NS). Even though atorvastatin had no effect on serum IL-6 levels (0.62 (0.37-0.88) pg/ml to 0.53 (0.28-0.73) pg/ml, p=NS), it significantly reduced circulating levels of IL-1b (from 1.17 (0.92-1.77) pg/ml to 1.02 (0.75-1.55) pg/ml, p<0.05) and sVCAM-1 (from 883.4 (660.3-1093.1) ng/ml to 801.4 (566.7-1030.2) ng/ml, p<0.05). No changes were seen in serum levels of IL-6, IL-1b and sVCAM-1 in the control group after 4 weeks compared with baseline (p=NS for all). CONCLUSIONS: Atorvastatin treatment for 4 weeks in subjects with SCR significantly improved endothelial function and suppressed systemic inflammatory status by decreasing circulating levels of IL-1b and sVCAM-1.

Exercise duration as a determinant of vascular function and antioxidant balance in patients with coronary artery disease.

BACKGROUND: Exercise improves the clinical outcome of patients with coronary artery disease (CAD); however, the ideal exercise duration for each patient remains unclear. OBJECTIVE: To investigate the effects of exercise duration on arterial elastic properties and antioxidant/pro-oxidant mechanisms in patients with CAD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Sixty male patients with CAD were randomised into two groups, and underwent exercise for 30 min or 60 min in a crossover design with 2 weeks' wash-out period. In all participants aortic and radial blood pressures (BP) and arterial elastic properties (augmentation index (AIx)/pulse wave velocity (PWV)) were determined at baseline and 24 h after exercise. Plasma malonyldialdehyde (MDA) and superoxide dismutase (SOD)1 and SOD2 levels were also measured. RESULTS: Exercise had no effect on aortic and radial BP (p=NS for all). Walking for 30 min improved AIx (from 33.79 ± 0.91% to 31.73 ± 0.86%, p<0.001) and PWV (from 9.26 ± 0.95 m/s to 9.06 ± 0.21 m/s, p<0.001), while exercise for 60 min had adverse effects on vascular stiffness (for AIx: from 33.37 ± 0.93% to 33.73 ± 1.05%, p=NS and for PWV: from 9.25 ± 0.19 m/s to 9.37 ± 0.21 m/s, p < 0.05 mainly in older patients). Exercise for 60 min was associated with a significant 20% increase in MDA levels (p<0.05). Exercise had no effects on SOD1 levels, however it significantly increased SOD2 levels after 30 min (from 2.26 ± 0.22 ng/mL to 2.36 ± 0.18 ng/mL, p < 0.05) but not after 60 min (p=NS). Conclusion Shorter exercise duration was associated with favourable antioxidant and vascular effects, while longer exercise blunted these beneficial effects and was accompanied by adverse effects on vascular function, mainly in older coronary patients. Further studies are required to explore the hypothesis that a more individualised approach to the selection of the appropriate exercise programme should be considered for patients with CAD.

Divergent anti-inflammatory effects of different oil acute consumption on healthy individuals.

BACKGROUND/OBJECTIVES: Inter-cellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and tumor necrosis factor-α (TNF-α), are implicated in atherogenesis. In addition, several types of oil as part of different types of diet are associated with the initiation of atherosclerosis and consequently with the risk of cardiovascular disease. However, the exact role of oil consumption on vascular inflammation remains unknown. In this parallel study, we assessed the acute effects of extra virgin olive oil, soy oil, corn oil and cod liver oil on circulating soluble(s) forms of adhesion molecules and TNF-α. SUBJECTS/METHODS: In all, 67 healthy volunteers were randomized to receive 50 ml of oil. Soluble forms of VCAM-1, ICAM-1 and TNF-α were measured by enzyme-linked immunosorbent assay at baseline and at 3 h post oil consumption. RESULTS: All types of oil had no significant effect on soluble VCAM-1 levels (P=nonsignificant (NS) for all). On the contrary, all oil types decreased ICAM-1 levels (P<0.01). Olive oil (P<0.05), soy oil and cod liver oil (P<0.01 for both) reduced TNF-α levels significantly, in contrast to corn oil, which induced a nonsignificant decrease (P=NS). Moreover, there was a significant correlation between the absolute change in ICAM-1 and TNF-α levels (ρ=0.379, P<0.05), but not between the absolute changes in VCAM-1 and TNF-α levels (ρ=0.019, P=NS). CONCLUSIONS: Acute consumption of all types of oil decreased significantly ICAM-1 levels. In addition, olive oil, soy oil and cod liver oil decreased significantly TNF-α levels. Moreover, the absolute change in TNF-α levels was correlated with the absolute change in ICAM-1 levels. These findings indicate that acute consumption of specific types of oil is associated with specific significant anti-inflammatory effects.

Endothelial dysfunction: potential clinical implications.

Vascular endothelium is responsible for the secretion of several substances exerting anti-atherogenic effects. Endothelial damage is also crucial for the progress of atherosclerosis and risk factors for atherosclerosis represent crucial factors associated with endothelial dysfunction. Studies have shown that patients with cardiovascular disease are characterized by impaired endothelial function (EF). Therefore, several agents have been proposed as potential modulators of EF. Most of the available approaches include pharmaceutical agents routinely used such as statins, angiotensin converting enzyme inhibitors, antioxidants, L-arginine, insulin sensitizers or others still under investigation such as tetrahydrobiopterin or folic acid (folate). Despite of the fact that there are several strategies aiming to improve endothelial dysfunction by enhancing nitric oxide bioavailability, it is still unclear whether they could be beneficial at a clinical level.

Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis.

BACKGROUND & AIM: Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti-inflammatory cytokine interleukin (IL)-10. We investigated the prognostic value of admission IL-10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro-inflammatory cytokines IL-6 and tumour necrosis factor (TNF)-alpha. METHODS: We measured these cytokines within 48 h of admission in 51 ALF and 39 decompensated cirrhosis patients admitted to intensive care, and obtained follow-up measurement a median of 2 days later in 35 patients. RESULTS: Levels of all cytokines were higher in those with a poor outcome. IL-10 performed as well as TNF-alpha and IL-6 in the whole cohort (area under receiver operator curve 0.73 vs 0.66 and 0.72). However IL-10 outperfomed pro-inflammatory cytokines in the subgroups with ALF (0.80 vs 0.63 and 0.70) and acetaminophen-induced ALF (0.92 vs 0.67 and 0.81). Levels of all cytokines rose significantly in non-surviving patients (n=15); IL-10 by a factor of 2, TNF-alpha by 2.6 and IL-6 by 1.13. No significant changes were seen in the surviving patients. In ALF, IL-10 was an independent predictor of outcome in multivariate analysis. CONCLUSION: The magnitude of the compensatory anti-inflammatory response at admission, and its development during the early phase of treatment, predicts outcome as well as the pro-inflammatory response in acute hepatic syndromes and supports a vital role for this immunological phenomenon in the outcome of these patients.

Circulating biomarkers for the diagnosis and prognosis of heart failure.

Despite substantial therapeutic advances, heart failure remains a syndrome associated with high morbidity and mortality. The management of heart failure remains challenging despite the recent different therapeutic advances. The emergence of cardiac biomarkers as increasingly effective clinical tools suggests the potential of a new approach to the management of patients with heart failure. A variety of circulating biomarkers of diagnostic and prognostic utility in heart failure is currently being studies in preclinical, observational and randomized prospective studies. Of the various candidate biomarkers, the greatest wealth of knowledge and clinical experience lies with the B-type naturetic peptides. However, because individual biomarkers may have limited sensitivity and specificity, a multi-marker approach, using combinations of different biomarkers that reflect different aspects of the pathophysiological milieu, would contribute to better risk stratification and optimization of therapy.

Adiponectin: from obesity to cardiovascular disease.

Adiponectin is an adipokine whose biosynthesis is deranged in obesity and diabetes mellitus, predisposing to atherosclerosis. Evidence suggests that adiponectin has anti-atherogenic properties by improving endothelial function and having anti-inflammatory effects in the vascular wall. In addition, adiponectin modifies vascular intracellular redox signalling and exerts indirect antioxidant effects on human myocardium. However, its clinical role in cardiovascular disease is obscure. Adiponectin's positive prognostic value in coronary artery disease had been widely supported over the last years, but this view has been questioned recently. High adiponectin levels are paradoxically associated with poorer prognosis in heart failure syndrome. These controversial findings seem surprising as adiponectin has been viewed overall as an anti-atherogenic molecule. Therefore, any certain conclusion about adiponectin's role in cardiovascular disease seems premature. Despite the rapidly accumulating literature on this adipokine, it is still unclear whether adiponectin is a key mediator or a bystander in cardiovascular disease. It is still uncertain whether adiponectin levels have any clinical significance for risk stratification in cardiovascular disease or they just reflect the activation of complex and opposing underlying mechanisms. Circulating adiponectin levels should be interpreted with caution, as they may have completely different prognostic value, depending on the underlying disease state.

Current and future management of chronic hepatitis C infection.

Current treatment for patients with chronic hepatitis C virus (HCV) infection consists of the combination of pegylated interferon and ribavirin. This treatment regimen achieves a sustained virological response, defined as undetectable HCV RNA 6 months after treatment cessation, in 50% of patients overall. There is therefore a need for new treatments to improve the sustained virological response rate and reduce the number of adverse effects associated with pegylated interferon and ribavirin. This review examines the current management of chronic HCV infection, including who is eligible for treatment, the optimum duration of treatment, and management of side effects. New drugs in development, such as HCV-specific protease inhibitors, polymerase inhibitors, immune modulators and ribavirin analogues, are outlined, and their role in the treatment armamentarium is discussed, whether used alone or in combination with existing treatments.