Current Pharmaceutical Design - Volume 24, Issue 3, 2018

Background: The term inflammatory joint disease (IJD) includes a group of chronic conditions, particularly rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA), with predominant joint involvement and increased risk of cardiovascular (CV) complications and premature mortality. Objective: The study aims to review of the most relevant CV manifestations from clinical point of view associated with IJD. Methods: To update the current knowledge on CV manifestations in patients with IJD, we review the most relevant literature studies published in English (PubMed database) from January 2007 to February 2017. Results: Ischemic heart disease and congestive heart failure are the most relevant complications and those causing higher mortality. Pericarditis and myocarditis may be seen in patients with RA, especially in flares of disease, although they are often asymptomatic. Left ventricular diastolic ventricular dysfunction is an increasing recognized problem. Arrhythmias and cardiac conduction disturbances may be observed in patients with IJD. Chronic inflammation and fibrosis of the cardiac conduction system may be responsible for these complications. Noninvasive diagnostic tools including cardiac magnetic resonance imaging and echocardiography have improved considerably our understanding of the cardiovascular disease in IJD. Conclusion: Cardiac manifestations in IJD are frequent and they are the leading cause of an increased morbimortality in IJD. Clinicians would be aware of that, given that early diagnosis of these complications may reduce the frequency of CV events and improve survival of patients with IJD.

Inflammation plays a significant role in atherosclerosis and cardiovascular disease (CVD). Patients with chronic inflammatory diseases are at increased risk of CVD, but it is debated whether this association is causal or dependent on shared risk factors, other exposures, genes, and/or inflammatory pathways. The current review summarizes epidemiological, clinical, and experimental data supporting the role of shared inflammatory mechanisms between atherosclerotic CVD and rheumatoid arthritis, psoriasis, inflammatory bowel disease, and periodontitis, respectively, and provides insights to future prospects in this area of research. Awareness of the role of inflammation in CVD in patients with chronic inflammatory diseases and the potential for anti-inflammatory therapy, e.g., with tumor necrosis factor-α inhibitors, to also reduce atherosclerotic CVD has evolved into guideline- based recommendations. These include regular CVD risk assessment, aggressive treatment of traditional CVD risk factors, and recognition of reduced CVD as an added benefit of strict inflammatory disease control. At present, chronic inflammatory diseases would appear to qualify as partners in crime and not merely innocent bystanders to CVD. However, definite incremental contributions of inflammation versus effects of the complex interplay with other CVD risk factors may never be fully elucidated and for the foreseeable future, inflammation is posed to maintain its current position as both a marker and a maker of CVD, with clinical utility both for identification of patient at risk of CVD and as target for therapy to reduce CVD.

In the last decades, the role of inflammation in the pathogenesis of atherosclerosis has been the topic of intense research. Several markers of inflammation have shown predictive value for first and recurrent coronary events in patients without and with established Coronary Heart Disease (CHD). Among these markers, lipoprotein- associated phospholipase A2 (Lp-PLA2) has recently received considerable attention. In the present review, the potential role of Lp-PLA2 as a marker of CHD risk and as a therapeutic target is discussed. Elevated Lp- PLA2 mass and activity appears to be associated with increased risk for CHD, both in the general population and in patients with established CHD. However, it is unclear whether the measurement of Lp-PLA2 improves risk discrimination when incorporated in models that include traditional cardiovascular risk factors. Moreover, the lack of effect on CHD events of darapladib, a potent, selective Lp-PLA2 inhibitor, in two large, randomized, placebo-controlled trials and the mostly negative findings of genetic association studies suggest that Lp-PLA2 is unlikely to represent a causal factor in atherogenesis. Therefore, it is doubtful whether Lp-PLA2 will constitute a therapeutic target for the prevention of CHD.

Epicardial adipose tissue is not only a specific adipose tissue depot but also an active endocrine organ producing numerous substances with an important role in the development of obesity-related heart diseases. It is located between myocardium and visceral pericardium and consists predominantly of adipocytes, immunocompetent cells, ganglia and interconnecting nerve branches. Several studies documented a positive correlation between pericardial and epicardial fat and left ventricular hypertrophy and septal thickening, leading to diastolic dysfunction, electrocardiographic abnormalities and facilitating cardiac failure. The cellular cross-talks between epicardial fat and myocardium may include both the vasocrine and the paracrine mechanisms. Adipokines secreted from epicardial adipose tissue, vascular and stromal cells diffuse into interstitial fluid crossing the adventitia, media and intima and modulate cardiac function and cardiomyocyte phenotype and survival. In this article, we review the significance of epicardial adipose tissue and its association with cardiovascular diseases, cellular interactions between epicardial fat and myocardium, secretions of adipokines and inflammatory mediators and a potential of epicardial fat as a therapeutic target for the prevention of obesity-related heart diseases.

Atrial fibrillation (AF) is a cardiac dysrhythmia commonly seen in clinical practice especially after cardiac surgery. It is associated with increased morbidity and mortality for the patients. The pathogenesis of AF is not exactly understood yet, but there is growing data about the relationship between AF and inflammation. Cardiac surgery itself is a big source for inflammation. It causes major surgical trauma, ischemia/reperfusion injury, hypothermia, low arterial pressure, and the equipment of cardiopulmonary bypass makes a large foreign surface thus it activates inflammatory response. There is a large number of data about the treatment options of AF and there are also strategies, which are related to reduction of inflammatory activation during cardiopulmonary bypass. In order to review the relationship between cardiac surgery, inflammation, AF and treatment strategies in patients with AF, we conducted a search through Pubmed for articles in English using the keywords: “atrial fibrillation, cardiac surgery, inflammation, medical therapy, surgical therapy, ablation therapy” from January 2012 to present. We also searched separately for each alternative treatment modality on Pubmed. To identify further articles, we also looked into related citations in review articles and commentaries. We searched thoroughly the guidelines published by the European Society of Cardiology (2016), and the American Heart Association/ American College of Cardiology/ Heart Rhythm Surgery (2014). Many studies concluded that inflammation contributes in the occurrence of AF. Inflammatory markers, such as CRP, interleukins and complements have high sensitivity and specificity for prediction of AF whether the patient having cardiac surgery or not. Betablockers, diltiazem and amiodarone are the most commonly used drugs for rate control in AF following surgery. Although there are some new therapeutic approaches to reduce postoperative inflammatory activation, such as the use of vitamins, fatty acids, statins, or technical improvements to cardiopulmonary bypass unit like miniaturized bypass circuits, heparin coating of the circuits, leukocyte filters, or various surgical approaches like off-pump coronary bypass surgery, we still need more effective strategies to reduce both postoperative inflammation and postoperative AF risk after cardiac surgery. Today we use more advanced invasive and surgical treatment strategies for AF although we need far more advanced technics to reduce perioperative inflammatory activation, which actually causes AF.

Polymyalgia rheumatica (PMR) represents the most common inflammatory rheumatic disease of the elderly. It is characterized by synovitis of proximal joints and extra-articular synovial structures, along with chronic high-grade systemic inflammation. PMR is closely related to giant cell arteritis (GCA), a large–vessel vasculitis that involves the major branches of the aorta, particularly the extracranial branches of carotid artery including temporal arteries. It is currently believed that PMR and GCA may represent different manifestations of the same disease process. Chronic systemic inflammation is presently recognized as one of the key pathogenic mechanisms underlying cardiovascular disease and associated complications, including cardiac arrhythmias and sudden death. In this regard, several studies demonstrated that besides promoting structural heart disease, inflammatory activation may also be per se arrhythmogenic, via cytokine-mediated effects on cardiac electrophysiology. In particular, increasing evidence points to inflammation as a novel risk factor for QTc prolongation and related life-threatening arrhythmias, specifically Torsade de Pointes (TdP). Starting from the report of two cases of TdP occurring in PMR patients with active disease and elevated circulating IL-6 levels, we here reviewed literature data regarding heart involvement and arrhythmic events in PMR/GCA, as well as TdP risk in inflammatory diseases. Potential underlying mechanisms were dissected, by focusing on the driving role of inflammatory activation.

Recently, numerous studies have found that particulate matter (PM) exposure is correlated with increased hospitalization and mortality from heart failure (HF). In addition to problems with circulation, HF patients often display high expression of cytokines in the failing heart. Thus, as a recurring heart problem, HF is thought to be a disorder characterized in part by the inflammatory response. In this review, we intend to discuss the relationship between PM exposure and HF that is based on inflammatory mechanism and to provide a comprehensive, updated evaluation of the related studies. Epidemiological studies on PM-induced heart diseases are focused on high concentrations of PM, high pollutant load exposure in winter, or susceptible groups with heart diseases, etc. Furthermore, it appears that the relationship between fine or ultrafine PM and HF is stronger than that between HF and coarse PM. However, fewer studies paid attention to PM components. As for experimental studies, it is worth noting that coarse PM may indirectly promote the inflammatory response in the heart through systematic circulation of cytokines produced primarily in the lungs, while ultrafine PM and its components can enter circulation and further induce inflammation directly in the heart. In terms of PM exposure and enhanced inflammation during the pathogenesis of HF, this article reviews the following mechanisms: hemodynamics, oxidative stress, Toll-like receptors (TLRs) and epigenetic regulation. However, many problems are still unsolved, and future work will be needed to clarify the complex biologic mechanisms and to identify the specific components of PM responsible for adverse effects on heart health.

Renal and cardiac function are greatly affected by chronic oxidative stress which can cause many pathophysiological states. The Na/K-ATPase is well-described as an ion pumping enzyme involved in maintaining cellular ion homeostasis; however, in the past two decades, extensive research has been done to understand the signaling function of the Na/K-ATPase and determine its role in physiological and pathophysiological states. Our lab has shown that the Na/K-ATPase signaling cascade can function as an amplifier of reactive oxygen species (ROS) which can be initiated by cardiotonic steroids or increases in ROS. Regulation of systemic oxidative stress by targeting Na/K-ATPase signaling mediated oxidant amplification improves 5/6th partial nephrectomy (PNx) mediated uremic cardiomyopathy, renal sodium handling, as well as ameliorates adipogenesis. This review will present this new concept of Na/K-ATPase signaling mediated oxidant amplification loop and its clinic implication.

The morbidity of myocarditis demonstrates an upward tendency by years, is commonly defined as the inflammation of myocytes and is caused by multiple factors. With the development of the molecular biological technique, great breakthroughs in the diagnosis and understanding of pathophysiological mechanisms of myocarditis have recently been achieved. Several questions remain unresolved, however, including standard treatment approaches to myocarditis, which remain controversial and ambiguous. Heart rate, as an independent risk factor, has been shown to be related to cardiac disease. Recent studies also show that the autonomic nervous system is involved in immunomodulatory myocarditis processes. Heart rate reduction treatment is recommended in myocarditis based on a number of animal experiments and clinical trials. It is possible that heart rate-lowering treatments can help to attenuate the inflammatory response and myocyte injury and reverse ventricular remodeling. However, how to execute the protective effects of heart rate reduction on myocarditis is still not clear. In this review, we discuss the pathogenesis and pathophysiological process of viral myocarditis and propose heart rate lowering as a therapeutic target for myocarditis, especially in light of the third-generation β-blockade carvedilol and funny channel blocker ivabradine. We also highlight some additional beneficial effects of such heart rate reduction agents, including anti-inflammatory, antioxidation, anti-nitrosative stress, anti-fibrosis and antiapoptosis properties.