Current Medicinal Chemistry (v.22, #23)

Inflammatory Biomarkers and Therapeutic Targets in Heart Failure by Lampros Papadimitriou, Andreas P. Kalogeropoulos (2716-2726).
Improved outcomes of acute cardiac conditions, population aging, prevalent lifestyle-related risk factors, and advances in heart failure (HF) therapy, all have led to an ever-increasing prevalence of HF, currently considered a public health priority in developed countries and a major noncommunicable syndrome in developing regions. Heart failure is a complex syndrome with a host of pathophysiological mechanisms in action. Inflammation, an integral component of homeostasis, is a complex tissue response to stressors that attempts to mitigate their effect and initiate healing. Inflammation plays a critical role in the development, course, severity and outcomes of HF. The delicate balance of pro- and antiinflammatory processes can lead to beneficial or detrimental effects to the failing heart. In this article, we review the evidence on inflammatory biomarkers and their potential role in prognosis and therapeutic decisions for patients with HF. Although attempts to directly disrupt the inflammatory cascade in HF have been largely abandoned due to lack of efficacy and potential harm, there are still important gaps in our knowledge. Despite the strong association of levels of inflammatory biomarkers with HF severity and comorbidities, the causal association of certain markers and pathways with specific types or aspects of HF remains to be elucidated. When used as treatment response markers in conjunction with other risk factors, inflammatory markers have the potential to improve risk stratification of patients with HF and personalize HF treatment, with the ultimate goal to improve quality of life and prolong survival in these patients.

Novel Inflammatory Markers in Hyperlipidemia: Clinical Implications by Angeliki Papapanagiotou, Gerasimos Siasos, Eva Kassi, Antonios N. Gargalionis, Athanasios G. Papavassiliou (2727-2743).
Hyperlipidemia is characterized by abnormally increased plasma of any or all lipids and /or lipoproteins and is a confirmed risk factor for the formation of atherosclerosis. Inflammation plays a crucial role in the formation and progression of atherosclerosis and consequently on cardiovascular diseases. Nowadays, the effective role of the immune system and subsequently of systemic inflammation is well established. Multiple levels of evidence from experimental models and histopathologic assessment of tissues to systemic biomarkers and epidemiologic or clinical associations have revealed that inflammation is one of the basic mechanisms in the destabilization of the atherogenetic plaque which leads to clinical events. Several inflammatory markers are affiliated with lipids level and the process of atherosclerosis. The most known of them are interleukin 6 and interleukin 1β, C-reactive protein, tumor necrosis factor-alpha, pentraxin3, serum amyloid A, sCD40, adhesion molecules, monocyte chemoattractant protein-1, sEndoglin, PAPP-A, chemokine 16, insulin like growth factor, lipoprotein-associated phospholipase A2 and galectin 3 but their role in atherogenesis is not well established for all of them. As atheromatosis is one of the main causes of death all over the world, in upcoming studies it will be useful to specify the exact role of these markers in this process in order to have a better prognosis, diagnosis and understanding of this disorder. The aim in this review is to study the literature on the novel inflammation markers of hyperlipidemia according to their clinical implications.

Peripheral artery disease (PAD) is an inflammatory disease caused by atherosclerosis. It has been demonstrated that PAD is related to chronic inflammation. While conventional risk factors lead to the pathogenesis and progression of PAD, the role of novel inflammatory biomarkers in relation to PAD is being increasingly recognized. The novel biomarkers for PAD may allow for earlier screening and detection, suppression of disease progression, and development of new therapeutic approaches. In this review, inflammatory biomarkers that should be contributory to diagnosis, prognosis, and avenues for therapeutic challenges in PAD are summarized.

Inflammation and Arterial Hypertension: From Pathophysiological Links to Risk Prediction by Panagiota Pietri, Charalambos Vlachopoulos, Dimitris Tousoulis (2754-2761).
Over the last years, ample data have demonstrated the pivotal role of low-grade inflammation in the pathophysiology of atherosclerosis and cardiovascular disease. It is well established that inflammatory activation, serving either as a substrate, in the chronic phase of atherosclerotic disease, or as a trigger, in the acute phase, increases cardiovascular events. Considering hypertension, the inflammatory process is implicated in its pathophysiology through a bidirectional relationship since arterial hypertension may enhance inflammation and vice versa. Inflammatory biomarkers such as highsensitivity C-reactive protein, have shown predictive value for both the incidence of hypertension and the clinical outcomes in hypertensive patients. In the present review, data on the association between arterial hypertension and low-grade inflammation will be reported and potential pathophysiological pathways and clinical implications underlying this association will be discussed.

Novel Inflammatory Indices in Aortic Disease by Manolis Vavuranakis, Maria Kariori, Dimitrios Vrachatis, Gerasimos Siasos, Konstantinos Kalogeras, Evelina Bei, Carmen Moldovan, Maria Lavda, Konstantinos Aznaouridis, Evangelos Oikonomou, Dimitris Tousoulis (2762-2772).
Inflammation plays a critical role in the atherosclerotic process in various vascular beds, starting from endothelial dysfunction and counting all stages of plaque development. The significant contribution of inflammation in the initiation and progression of atherosclerosis has been documented over many years but its contribution to the development of other cardiovascular disease remains unclear. Inflammatory process constitutes a basic part of pathogenic cascade of aortic diseases including those of aortic valve stenosis and aortic aneurysms. Thus, both of these entities are related with high rates of morbidity and mortality. Therefore, the need to detect and investigate indices representative of inflammation that will be easily measured and may reflect the process of these diseases, is mandatory. However, such biomarkers for aortic diseases that could have a significant prognostic value on survival via the early identification of high risk patients, in general, remain few. Therefore, the illumination of role of such biomarkers, will facilitate the understanding of the mechanisms in molecular and/or cellular level that are responsible for the creation of aortic disease. Such an approach may provide a pathophysiological basis for early diagnosis.

Novel Inflammatory Biomarkers in Cardiovascular Therapeutics by Vicky Tsigkou, Gerasimos Siasos, Evangelos Oikonomou, Marina Zaromitidou, George Latsios, Manolis Vavuranakis, Spyridon Deftereos, Michael W. Cleman, Eleni Kokkou, Maria Limberi, Stathis Dimitropoulos, Thodoris Zografos, Smaragdi Marinaki, Christodoulos Stefanadis, Dimitris Tousoulis (2773-2785).
Inflammation has been established as an important determinant of cardiovascular disease progression. Currently, clinical examination, laboratory and imaging tests are invaluable for the diagnosis, prognosis and disease monitoring. Novel inflammatory biomarkers are also used to better restratify patients in risk groups but their potential to guide treatment decisions and management of patients has not been extensively evaluated. Therefore, in this review article we present the most recent data concerning the use of inflammatory biomarkers in cardiovascular therapeutics.

The Importance of Novel Inflammatory Biomarkers in Renal Disease by S. Marinaki, C. Skalioti, Gerasimos Siasos, Athanasios G Papavassiliou, Dimitris Tousoulis, J.N. Boletis (2786-2800).
Kidney disease, whether acute or chronic, represents a major health hazard. Acute kidney injury (AKI) detection is based mainly on serum creatinine, which is considered to delay prompt diagnosis and management, thus increasing substantially patient morbidity and mortality and prolonged hospitalization. Several biomarkers have been evaluated as early prognostic markers of AKI. However, the vast majority of them are still far from being implicated into clinical practice. On the other hand, routine eGFR estimation and proteinuria monitoring have contributed to previous identification of chronic kidney disease (CKD). Hence, more sensitive and specific biomarkers are needed to enable us recognize individuals at increased risk for progression of CKD to end-stage renal disease (ESRD) and occurrence of cardiovascular complications. This review focuses on the most important novel inflammatory biomarkers that have emerged for early prediction, monitoring and management of kidney disease.

Adrenal Insufficiency Caused by Locally Applied Glucocorticoids-Myth or Fact? by Stina Willemoes Borresen, Marianne Klose, Ase Krogh Rasmussen, Ulla Feldt-Rasmussen (2801-2809).
Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids have been shown to cause adrenal suppression in 0-16% of patients. Glucocorticoid creams and nasal glucocorticoids can cause adrenal insufficiency, also when used within prescribed doses, but the frequency seems to be less than with inhaled glucocorticoids. Intraarticularly administered glucocorticoids can cause adrenal suppression after a single injection. The systemic effect of locally applied glucocorticoids depends on pharmacokinetic and -dynamic properties of the particular glucocorticoid as well as individual factors. Many of the symptoms in iatrogen adrenal insufficiency are unspecific and often difficult to differentiate from symptoms of underlying disease activity. The condition might therefore be more common than widely believed and underdiagnosed in clinical practice. Potential adrenal insufficiency must therefore always be kept in mind in patients treated with all forms of glucocorticoids. Clinically important points and patient management are discussed on the basis of a case report and review of the literature. More work assessing the prevalence of adrenal insufficiency secondary to locally applied glucocorticoids is urgently needed.