Clinical Utility of Rilonacept for the Treatment of Recurrent Pericarditis: Design, Development, and Place in Therapy.

Recurrent pericarditis (RP) has been traditionally regarded as a "nightmare" for both clinicians and patients. Until approximately a decade ago, available treatments were thin on the ground with non-steroidal anti-inflammatory medications, glucocorticoids, colchicine, and classical immunosuppressants being the only options. The first important step in the tale of RP was the advent of colchicine in clinical practice, which has been shown to halve the rate of first and subsequent pericarditis recurrences. The second major breakthrough advance in this setting was the introduction of interleukin-1 inhibitors based on the recently unveiled autoinflammatory nature of pericarditis. At present, anti-interleukin-1 inhibitors available for clinical use in patients with refractory RP include anakinra and rilonacept, with the latter having obtained FDA approval for this indication. Apart from the remarkable efficacy and good safety profile which is a common feature of all anti-interleukin-1 compounds, rilonacept has the advantage of weekly administration (instead of daily compared to anakinra) which is important in terms of adherence to treatment and improved quality of life albeit at the expense of a higher cost. This review aims to summarize the available evidence on the role of rilonacept in the treatment of RP and the reduction of the recurrences risk.

Effect of FluoRoquinolones on Aortic Growth, aortic stIffness and wave refLEctionS (FRAGILES study).

Background: The widespread use of fluoroquinolones has been associated with the formation, dissection, and rupture of aortic aneurysms. Arterial biomarkers are established predictors of cardiovascular events. The present study was designed to investigate the effect of quinolones on arterial stiffness and aortic size for the first time. Methods: We studied 28 subjects receiving short-term (<15 days) antibiotic therapy involving quinolones and 27 age- and sex-matched subjects receiving an alternative to quinolone antibiotics. The follow-up period was approximately 2 months. The study's primary endpoint was the carotid-femoral pulse wave velocity (cfPWV) difference between the two groups 2 months after therapy initiation. Secondary endpoints were the augmentation index corrected for heart rate (AIx@75) and sonographically assessed aortic diameters 2 months after the initial treatment. Results: Subjects had similar values of arterial biomarkers, blood pressure measurements, and aortic diameters at baseline. At follow-up, no significant change was observed between the two groups regarding the hemodynamic parameters and arterial biomarkers (p > 0.05 for all), i.e., cfPWV (7.9 ± 2.6 m/s for the control group vs. 8.1 ± 2.4 m/s for the fluoroquinolones group; p = 0.79), AIx@75 (22.6 ± 9.0% for the control group vs. 26.6 ± 8.1% for the fluoroquinolones group; p = 0.09), and aortic diameters. Conclusions: To our knowledge, FRAGILES is the first study to provide insights into the possible effects of fluoroquinolones on arterial biomarkers, showing that, at least in the short term, treatment with fluoroquinolones does not affect aortic function and diameter.

Novel Treatments in Refractory Recurrent Pericarditis.

Refractory recurrent pericarditis is a troublesome condition that severely impairs the quality of life of affected patients and significantly increases healthcare spending. Until recently, therapeutic options included only a few medications and most of the patients resorted to chronic glucocorticoid treatment with steroid dependence. In the most recent decade, the introduction of interleukin-1 blockers in clinical practice has revolutionized the treatment of glucocorticoid-dependent and colchicine-resistant recurrent pericarditis due to their excellent efficacy and good safety profile. The rationale for the introduction of this class of medications in clinical practice is the autoinflammatory nature of recurrent pericarditis in a substantial rate of cases, with interleukin-1 being the main pro-inflammatory cytokine involved in this context. This review aims to discuss the contemporary available evidence from original research and real-world data on interleukin-1 blocker use in refractory recurrent pericarditis, in terms of indications, mechanism of action, efficacy, side effects, and recommended treatment protocols. Moreover, novel treatment proposals, such as hydroxychloroquine, beta blockers, and cannabidiol, which showed encouraging preliminary results, are addressed. Finally, gaps in knowledge, unmet needs, and future perspectives related to recurrent pericarditis are thoroughly discussed.

Asymptomatic Chronic Large Pericardial Effusions: To Drain or to Observe?

Pericardial effusions, especially large ones, have traditionally been regarded with concern by clinicians due to the sometimes unpredictable development of life-threatening cardiac tamponade. In the European Society of Cardiology Guidelines on pericardial diseases, the simplified algorithm for pericardial effusion triage and management recommends pericardial drainage in cases of cardiac tamponade and/or suspicion of bacterial or neoplastic etiology. In the presence of acute pericarditis, empiric anti-inflammatory treatment should be given, while when a specific indication known to be associated with pericardial effusion is found, then treatment of the underlying cause is indicated. Notably, the most challenging subgroup of patients includes those with large, asymptomatic, C-reactive-protein-negative, idiopathic effusions. In the latter subjects, pericardial drainage is proposed in cases of chronic effusions (lasting more than three months). However, this recommendation is based on scant data stemming from small-sized non-randomized studies. Nevertheless, recent evidence in a larger cohort of patients pointed out that a watchful waiting strategy is a safe option in terms of complication-free survival. This review summarizes the contemporary evidence on this challenging topic and provides recommendations for tailoring individual patient treatments.

Interleukin-1 Blockers: A Paradigm Shift in the Treatment of Recurrent Pericarditis.

Recurrent pericarditis is a problematic clinical condition that impairs the quality of life of the affected patients due to the need for repeated hospital admissions, emergency department visits, and complications from medications, especially glucocorticoids. Unfortunately, available treatments for recurrent pericarditis are very limited, including only a handful of medications such as aspirin/NSAIDs, glucocorticoids, colchicine, and immunosuppressants (such as interleukin-1 (IL-1) blockers, azathioprine, and intravenous human immunoglobulins). Until recently, the clinical experience with the latter class of medications was very limited. Nevertheless, in the last decade, experience with IL-1 blockers has consistently grown, and valid clinical data have emerged from randomized clinical trials. Accordingly, IL-1 blockers are a typical paradigm shift in the treatment of refractory recurrent pericarditis with a clearly positive cost/benefit ratio for those unfortunate patients with multiple recurrences. A drawback related to the above-mentioned medications is the absence of universally accepted and established treatment protocols regarding the full dose administration period and the need for a tapering protocol for individual medications. Another concern is the need for long-standing treatments, which should be discussed with the patients. The above-mentioned unmet needs are expected to be addressed in the near future, such as further insights into pathophysiology and an individualized approach to affected patients.

Inflammatory Mediators of Endothelial Dysfunction.

Endothelial dysfunction (ED) is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and inflammatory factors, as well as deficiency of nitric oxide (NO) bioavailability. It has been reported that the maintenance of endothelial cell integrity serves a significant role in human health and disease due to the involvement of the endothelium in several processes, such as regulation of vascular tone, regulation of hemostasis and thrombosis, cell adhesion, smooth muscle cell proliferation, and vascular inflammation. Inflammatory modulators/biomarkers, such as IL-1α, IL-1ß, IL-6, IL-12, IL-15, IL-18, and tumor necrosis factor α, or alternative anti-inflammatory cytokine IL-10, and adhesion molecules (ICAM-1, VCAM-1), involved in atherosclerosis progression have been shown to predict cardiovascular diseases. Furthermore, several signaling pathways, such as NLRP3 inflammasome, that are associated with the inflammatory response and the disrupted H2S bioavailability are postulated to be new indicators for endothelial cell inflammation and its associated endothelial dysfunction. In this review, we summarize the knowledge of a plethora of reviews, research articles, and clinical trials concerning the key inflammatory modulators and signaling pathways in atherosclerosis due to endothelial dysfunction.

D-dimer as a diagnostic and prognostic plasma biomarker in patients with a first episode of acute pericarditis.

OBJECTIVES: The impact of plasma biomarkers on diagnosis and prognosis of patients with acute pericarditis (AP) has been poorly investigated. This study aims to assess the diagnostic and prognostic role of d-dimer (DD), an easily obtainable biomarker, in patients with AP. PATIENTS AND METHODS: This is a prospective clinical study enrolling 265 consecutive patients hospitalized between September 2010 and May 2019 with a first episode of AP. At baseline, demographics, clinical features, laboratory and imaging findings were recorded. All patients were followed-up for a minimum of 18 months. Endpoints included cardiac tamponade, new-onset atrial fibrillation, pericardial drainage, recurrent/constrictive pericarditis and death. RESULTS: DD was measured in 165 out of 265 patients (62.3%, median levels 1456 ng/mL) Among them, 121 patients (73.3%) presented with elevated age-adjusted DD levels. Patients with elevated DD depicted a higher rate of pleural (69.4%, vs 38.6%, p<0.001) and pericardial effusions (89.3% vs 72.7%, p = 0.009). Elevated DD correlated with admission (rho=0.37) and peak (rho=0.36) C-reactive protein values. Patients with elevated DD depicted a trend towards a greater prevalence of pericardial tamponade vs those without (14.9% vs 4.5% respectively, p = 0.07). In the 43.8% of patients with elevated DD who underwent computed tomography pulmonary angiography (CTPA), no case of pulmonary embolism or aortic syndrome was unveiled. CONCLUSION: DD elevation is detected in the majority of AP cases at presentation and may herald cardiac tamponade. In patients with chest pain not attributable to alternative causes, elevated DD denotes an inflammatory condition and should not prompt unnecessary investigations, such as CTPA.

Lipoprotein(a), metabolic profile and new-onset type 2 diabetes in patients with familial combined hyperlipidemia: A 9 year follow-up study.

BACKGROUND: Lipoprotein(a) [Lp(a)] appears to have an inverse association with the risk of type 2 diabetes mellitus in the general population. OBJECTIVE: This study aimed to investigate the prognostic role of Lp(a) regarding the development of type 2 diabetes in the special population of subjects with familial combined hyperlipidemia (FCH). METHODS: This cohort study included 474 patients (mean age 49.7±11.3 years, 64% males) with FCH, without diabetes at baseline who were followed for a mean period of 8.2±6.8 years. At baseline evaluation venous blood samples were obtained for the determination of lipid profile and Lp(a) levels. The endpoint of interest was the development of diabetes. RESULTS: Patients with increased Lp(a) levels ≥30 mg/dl compared to those with low Lp(a) levels <30 mg/dl had lower levels of triglycerides (238±113 vs 268±129 mg/dl, p = 0.01), greater levels of high-density lipoprotein (HDL) cholesterol (44±10 vs 41±10 mg/dl, p = 0.01) and hypertension in a greater percentage (42% vs 32%, p = 0.03). The incidence of new-onset diabetes during the follow-up period was 10.1% (n = 48). Multiple Cox regression analysis revealed that increased Lp(a) is an independent predictor of lower diabetes incidence (HR 0.39, 95% CI 0.17-0.90, p = 0.02) after adjustment for confounders. CONCLUSION: Among subjects with FCH those with higher Lp(a) levels have lower risk for the development of type 2 diabetes. Moreover, the presence of increased Lp(a) seems to differentiate the expression of metabolic syndrome characteristics in patients with FCH, as increased Lp(a) is related to lower levels of triglycerides, greater prevalence of hypertension and higher levels of HDL cholesterol.

Cardiomyopathies in children: An overview.

Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.

Chronic Pericardial Effusion: Causes and Management.

Chronic pericardial effusion is a common pericardial syndrome whose approach has been well standardised in recent years. The main challenge associated with this condition is the progression (sometimes unheralded) to cardiac tamponade. Pericardial effusions may present either as an isolated finding or in the context of a specific etiology including autoimmune, neoplastic, or metabolic disease. Among investigations used during diagnostic work-up, echocardiography is of paramount importance for the diagnosis, sizing, and serial evaluation of the hemodynamic impact of effusions on heart diastolic function. In an individualised manner, advanced imaging including computed tomography and cardiac magnetic resonance imaging should be performed, especially if baseline tests are inconclusive. Triage of these patients according to the most recent 2015 European Society of Cardiology Guidelines for the diagnosis and management of pericardial diseases should take into account the presence of hemodynamic compromise as well as suspicion of malignant or purulent pericarditis as first step, C-reactive protein serum level measurement as second step, investigations for a specific condition known to be associated with pericardial effusion as third step, and finally the size and the duration of the effusion. Treatment depends on the evaluation of the above-mentioned parameters and should ideally be tailored to the individual patient. Prognosis of chronic pericardial effusions depends largely on the underlying etiology. According to novel data, the prognosis of individuals with idiopathic, chronic (> 3 months), large (> 2 cm), asymptomatic pericardial effusions is usually benign and a watchful waiting strategy seems more reasonable and cost-effective than routine drainage as previously recommended.

Lipoprotein-associated Phospholipase A2 in Coronary Artery Disease.

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in western societies. Therefore the identification of novel biomarkers to be used as diagnostic or therapeutic targets is of significant scientific interest. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is one such protein shown to be involved in endothelial dysfunction, vascular inflammation and atherogenesis. Several epidemiological studies have associated high Lp-PLA2 activity with an increased risk for CAD even when other CAD risk factors or inflammation markers were included in the multivariate analysis. These findings were strengthened by the results of relevant meta-analyses. However, randomized trials failed to establish Lp-PLA2 as a therapeutic target. Specifically, pharmaceutical inhibition of Lp-PLA2 when compared to the placebo failed to demonstrate a significant association with improved prognosis of patients with stable CAD or after an acute coronary syndrome (ACS). This review focuses on the available data that have investigated the potential role of Lp- PLA2 as a biomarker for CAD.

Aspirin for Primary Prevention of Cardiovascular Diseases: "WALTZ" with the Evidence.

PURPOSE OF REVIEW: In this review article, a detailed analysis of the current literature is provided, along with a "glimpse" into what the future holds for aspirin in the context of primary prevention. RECENT FINDINGS: The role of aspirin in primary prevention of cardiovascular diseases (CVD) has been extensively evaluated; however, the results provided over the years have been controversial. Identification of individual subgroups who may benefit from aspirin administration at an acceptable risk of bleeding complications is of paramount importance. Additionally, questions emerge at everyday clinical practice regarding the optimal use of aspirin in different phenotypes of patients due to age, sex, obesity status, frailty and diabetes mellitus. Until further data become available, the effective management of the well-established CV risk factors constitutes the milestone in the primary prevention of CVD. Moreover, based on the available evidence, the beneficial addition of aspirin in the modern era of lifestyle and pharmacological interventions for primary CVD prevention remains largely undetermined and further research is needed.

Acute Pericarditis: Update.

PURPOSE OF REVIEW: Since 2015, when ESC guidelines for the diagnosis and management of pericardial diseases were published, ongoing research has enhanced the current state of knowledge on acute pericarditis. This review is an update on the latest developments in this field. RECENT FINDINGS: In recurrent acute pericarditis, autoinflammation has been included among causative mechanisms restricting the vague diagnoses of "idiopathic" pericarditis. Cardiac magnetic resonance that detects ongoing pericardial inflammation may guide treatment in difficult-to-treat patients. Development of risk scores may assist identification of patients at high risk for complicated pericarditis, who should be closely monitored and aggressively treated. Treatment with IL-1 inhibitors has been proven efficacious in recurrent forms with a good safety profile. Finally, acute pericarditis has recently attracted great interest as it has been reported among side effects post COVID-19 vaccination and may also complicate SARS-CoV-2 infection. Recent advancements in acute pericarditis have contributed to a better understanding of the disease allowing a tailored to the individual patient approach. However, there are still unsolved questions that require further research.

Chronic pericardial effusion: current concepts and emerging trends.

INTRODUCTION: Pericardial effusion (PEF) is a common and challenging pericardial syndrome with a variety of clinical manifestations ranging from asymptomatic, incidentally uncovered small PEFs, to life-threatening cardiac tamponade. AREAS COVERED: This review focuses on the pathophysiology, epidemiology, aetiology, classification, clinical findings, diagnostic work-up, management, and outcome of PEFs. Particular emphasis has been given on the most recent evidence concerning the contribution of imaging for the detection, differential diagnosis, and evaluation of the haemodynamic impact of PEFs on the diastolic filling of the heart. Moreover, simplified algorithms for PEF triage and management have been included. EXPERT OPINION: The management of patients with PEFs is mainly based on four parameters, namely, haemodynamic impact on diastolic function, elevation of inflammatory markers, presence of a specific underlying condition known to be associated with PEF, and finally size and duration of the effusion. Novel data have contributed to change our view towards large, asymptomatic, 'idiopathic' PEFs and dictated a rather conservative approach in most cases. It is also stressed that there is a compelling need for additional research, which is essential for tailored treatments aiming at the improvement of quality of life and containment of health care costs.

Overview of Chios Mastic Gum (Pistacia lentiscus) Effects on Human Health.

Despite the remarkable development of the medical industry in the current era, herbal products with therapeutic potentials arise as attractive alternative treatments. Consequently, Chios mastiha, a natural, aromatic resin obtained from the trunk and brunches of the mastic tree, has recently gained increasing scientific interest due to its multiple beneficial actions. Chios mastiha is being exclusively produced on the southern part of Chios, a Greek island situated in the northern Aegean Sea, and its therapeutic properties have been known since Greek antiquity. There is now substantial evidence to suggest that mastiha demonstrates a plethora of favorable effects, mainly attributed to the anti-inflammatory and anti-oxidative properties of its components. The main use of mastiha nowadays, however, is for the production of natural chewing gum, although an approval by the European Medicines Agency for mild dyspeptic disorders and for inflammations of the skin has been given. The aim of this article is to summarize the most important data about the therapeutic actions of Chios mastiha and discuss future fields for its medical application.

Role of genetic testing in cardiomyopathies: Α primer for cardiologists.

Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies. As novel mutations have been identified, understanding when to consider genetic testing has emerged as an important consideration in the management of these cases. Specific genetic testing has a paramount importance in the risk stratification of family members, in the prognosis of probands at higher risk of a serious phenotype expression, and finally in the identification of new mutations, all of which are discussed in this review. The indications for each type of cardiomyopathy are described, along with the limitations of genetic testing. Finally, the importance of public sharing of variants in large data sets is emphasized. The ultimate aim of this review is to present key messages about the genetic testing process in order to minimize potential harms and provide suggestions to specialized clinicians who act as a part of a multidisciplinary team in order to offer the best care to families with inherited cardiomyopathies.

Pericarditis and pericardial effusion: one or two distinct diseases?

The main pericardial syndromes include acute and recurrent pericarditis, constrictive pericarditis, and chronic pericardial effusion in the absence of overt inflammation. Despite recent advances in pericardial syndromes, certain clinical scenarios depict remarkable peculiarities, and their management is often challenging for the clinician. Acute pericarditis is the most common pericardial disease and in most instances is accompanied by pericardial effusion. On the other hand, pericardial effusion may appear as a separate clinical entity occasionally characterized by absence of inflammatory markers elevation. In cases that effusions are accompanied by C-reactive protein (CRP) elevation, the administration of empiric anti-inflammatory treatment as in acute pericarditis, is the guidelines recommended approach. Conversely, the optimal management of patients with pericardial effusions in the absence of clinical or subclinical inflammation (as depicted by CRP levels and cardiac magnetic resonance findings), is not supported by solid evidence. Patients with chronic pericardial effusions should be followed in specialized centers according to tailored timelines, based on the specific clinical scenarios which should consider etiology, effusion size, disease duration and stability as regards symptoms and effusion volume. Patients should also be advised to seek medical care at any time if symptoms like chest pain, dyspnea and fatigue should appear.

Incidence and Prevalence of Cardiac Arrhythmias in Pericardial Syndromes.

Arrhythmias in pericardial syndromes have been poorly investigated and available data are mainly obtained from relevant studies however having different endpoints from arrhythmias. Thus, the incidence and prevalence of any type of arrhythmias may be actually higher than generally considered. Atrial arrhythmias, mainly atrial fibrillation and flutter have been reported as the most common rhythm disturbances in the setting of acute pericarditis. Concerning pathophysiology of atrial arrhythmias, in contrast to earlier hypothesis that they occur exclusively in the presence of an underlying structural heart disease, recent data support an arrhythmogenic potential of acute pericardial inflammation regardless of the presence of heart disease. In cases of myopericarditis, namely primarily pericarditis with evidence of myocardial involvement (i.e., troponin elevation without however overt left ventricular dysfunction and/or segmental wall motion abnormalities), ventricular arrhythmias appear to prevail. With reference to the rest of pericardial syndromes data on arrhythmias development are even more sparce. In particular, in constrictive pericarditis atrial tachyarrhythmias are the most commonly detected and seem to be related to disease severity and possibly to the underlying etiology. In this review we have summarized the available information on the incidence and prevalence of arrhythmias in pericardial syndromes. We wish to emphasize that the clinical significance of arrhythmias in this setting in terms of prognosis and optimal medical treatment (including need and safety of anticoagulation in atrial fibrillation/flutter complicating acute pericarditis), should be further investigated.