Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem.

Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and nonischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions has been increasingly explored, giving rise to the field of senotherapeutics. Therefore, we additionally attempt to clarify the current state of this field with a focus on cardiac senescence and discuss the potential of implementing senolytics as a treatment option in heart disease.

Molecular biomarkers in cardio-oncology: Where we stand and where we are heading.

Until recently, cardiotoxicity in the setting of a malignant disease was attributed solely to the detrimental effects of chemo- and/or radio-therapy to the heart. On this account, the focus was on the evaluation of well-established cardiac biomarkers for the early detection of myocardial damage. Currently, this view has been revised. Cardiotoxicity is not restricted to a single organ but instead affects the endothelium as a whole. Indeed, it has come into light that not only cancer therapy but also malignant cells per se can impair the cardiovascular system, through a paracrine and endocrine mode of action. Even more intriguingly, a clear interplay between molecular pathways involved in cancer and cardiovascular disease has become prevalent, suggesting a common nominator that governs the pathophysiology of these two entities. Taken together, our strategy in the quest of novel biomarkers in the emerging field of cardio-oncology should be critically reshaped.

A risk score for pericarditis recurrence.

BACKGROUND: Currently, we remain uncertain about which patients are at increased risk for recurrent pericarditis. We developed a risk score for pericarditis recurrence in patients with acute pericarditis. MATERIALS AND METHODS: We prospectively recruited 262 patients with a first episode of acute pericarditis. Baseline patients' demographics, clinical, imaging and laboratory data were collected. Patients were followed up for a median of 51 months (interquartile range 21-71) for recurrence. Variables with <10% missingness were entered into multivariable logistic regression models with stepwise elimination to explore independent predictors of recurrence. The final model performance was assessed by the c-index whereas model's calibration and optimism-corrected c-index were evaluated after 10-fold cross-validation. RESULTS: We identified six independent predictors for pericarditis recurrence, that is age, effusion size, platelet count (negative predictors) and reduced inferior vena cava collapse, in-hospital use of corticosteroids and heart rate (positive predictors). The final model had good performance for recurrence, c-index 0.783 (95% CI 0.725-0.842), while the optimism-corrected c-index after cross-validation was 0.752. Based on these variables, we developed a risk score point system for recurrence (0-22 points) with equally good performance (c-index 0.740, 95% CI 0.677-0.803). Patients with a low score (0-7 points) had 21.3% risk for recurrence, while those with high score (≥12 points) had a 69.8% risk for recurrence. The score was predictive of recurrence among most patient subgroups. CONCLUSIONS: A simple risk score point system based on 6 variables can be used to predict the individualized risk for pericarditis recurrence among patients with a first episode of acute pericarditis.

Prognostic implications of epicardial fat volume quantification in acute pericarditis.

BACKGROUND: The pathophysiology of acute pericarditis remains largely unknown, and biomarkers are needed to identify patients susceptible to complications. As adipose tissue has a pivotal role in cardiovascular disease pathogenesis, we hypothesized that quantification of epicardial fat volume (EFV) provides prognostic information in patients with acute pericarditis. MATERIALS AND METHODS: Fifty (n = 50) patients with first diagnosis of acute pericarditis were enrolled in this study. Patients underwent a cardiac computerized tomography (CT) scan to quantify EFV on a dedicated workstation. Patients were followed up in hospital for atrial fibrillation (AF) development and up to 18 months for the composite clinical endpoint of development of constrictive, recurrent or incessant pericarditis or poor response to nonsteroidal anti-inflammatory drugs. RESULTS: Patients presenting with chest pain had lower EFV vs. patients without chest pain (167·2 ± 21·7 vs. 105·1 ± 11·1 cm3 , respectively, P < 0·01); EFV (but not body mass index) was strongly positively correlated with pericardial effusion size (r = 0·395, P = 0·007) and associated with in-hospital AF. At follow-up, patients that reached the composite clinical endpoint had lower EFV (P < 0·05). After adjustment for age, EFV was associated with lower odds ratio for the composite clinical endpoint point of poor response to NSAIDs or the development of constrictive, recurrent or incessant pericarditis during follow-up (per 20 cm3 increase in EFV: OR = 0·802 [0·656-0·981], P < 0·05). CONCLUSIONS: We report for the first time a significant association of EFV with the clinical features and the outcome of patients with acute pericarditis. Measurement of EFV by CT may have important prognostic implications in these patients.

Principal Aspects Regarding the Maintenance of Mammalian Mitochondrial Genome Integrity.

Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial dysfunction is a hallmark in the pathogenesis of various diseases. Mitochondrial biogenesis and function require the coordinated action of two genomes: nuclear and mitochondrial. Unfortunately, both intrinsic and environmental genotoxic insults constantly threaten the integrity of nuclear as well as mitochondrial DNA. Despite the extensive research that has been made regarding nuclear genome instability, the importance of mitochondrial genome integrity has only recently begun to be elucidated. The specific architecture and repair mechanisms of mitochondrial DNA, as well as the dynamic behavior that mitochondria exert regarding fusion, fission, and autophagy participate in mitochondrial genome stability, and therefore, cell homeostasis.

Erythropoietin administration facilitates return of spontaneous circulation and improves survival in a pig model of cardiac arrest.

BACKGROUND: In addition to its role in the endogenous control of erythropoiesis, recombinant human erythropoietin (rh-EPO) has been shown to exert tissue protective properties in various experimental models. However, its role in the cardiac arrest (CA) setting has not yet been adequately investigated. AIM: The aim of this study is to examine the effect of rh-EPO in a pig model of ventricular fibrillation (VF)-induced CA. METHODS: Ventricular fibrillation was electrically induced in 20 piglets and maintained untreated for 8 minutes before attempting resuscitation. Animals were randomized to receive rh-EPO (5000 IU/kg, erythropoietin [EPO] group, n = 10) immediately before the initiation of chest compressions or to receive 0.9% Sodium chloride solution instead (control group, n = 10). RESULTS: Compared with the control, the EPO group had higher rates of return of spontaneous circulation (ROSC) (100% vs 60%, P = .011) and higher 48-hour survival (100% vs 40%, P = .001). Diastolic aortic pressure and coronary perfusion pressure during cardiopulmonary resuscitation were significantly higher in the EPO group compared with the control group. Erythropoietin-treated animals required fewer number of shocks in comparison with animals that received normal saline (P = .04). Furthermore, the neurologic alertness score was higher in the EPO group compared with that of the control group at 24 (P = .004) and 48 hours (P = .021). CONCLUSION: Administration of rh-EPO in a pig model of VF-induced CA just before reperfusion facilitates ROSC and improves survival rates as well as hemodynamic variables.

Patients' Satisfaction With Pharmaceutical Care Services Provided During COVID Pandemic: Experience From Greece.

Introduction Private pharmacies can contribute to the health care system through primary care. Purpose The purpose of this study is to determine patients' expectations of pharmaceutical care services during covid pandemic in order to measure the level of patient satisfaction provided by the Greek healthcare system. Also, it is important to identify the associated factors that might affect patient satisfaction. Material and Method The sample of the study consisted of 168 customers of pharmacies in Athens. A patient satisfaction survey was conducted at health facilities operating in Athens. Data regarding socio-demographic characteristics and parameters that measure patients' expectations and satisfaction were collected through a closed-ended questionnaire that had been tested for validity and reliability. The patient's point of view was evaluated based on their expectation and perception of the pharmaceutical care services they had received. Data were entered into SPSS version 22 (IBM Corp, Armonk, NY ), and descriptive statistics, cross-tabs, and binary logistic regressions were utilized. P < 0.05 was used to declare association. Results About 89.3% of the participants were insured in the Greek health system. The main reason for visiting the pharmacy was the purchase of medicines and products (95.2%), vaccinations (19.6%), and consulting services for first aid (17.3%). The pharmacist was rated for his courtesy, willingness, friendliness, and reliability. Only 48.2% of participants knew that the pharmacy provided primary care services during the pandemic. The most common services provided were blood pressure measurement and intramuscular injections. Around 64.2% of them were fully satisfied. Pharmacists in primary care teams are uniquely positioned to facilitate practice expansion and make medicine a trusted resource for physicians, as well as improve health outcomes for patients. Conclusions The pharmacy has a leading role in health care due to easy access, and fast and immediate service. Patient-clients in Greek society trust their pharmacist as a health professional. Further research is suggested to ensure that through the delivery of health services by pharmacies, the cost of primary care could be lower.

The Predictive Role of Cardiac Troponin in Non-cardiac Surgery: A Study in the Greek Population.

Introduction The incidence of postoperative myocardial ischemia (POMI) remains uncertain and underdiagnosed despite significant morbidity and mortality rates. Methods This study included patients who underwent non-cardiac surgery. Troponin T (TnT) was measured on the first three postoperative days. The revised cardiac risk index, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio (INR), elderly, drugs/alcohol concomitantly) bleeding score, and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack (TIA), vascular disease, age 65 to 74 years, sex category) score were combined. The receiver operating characteristic (ROC) curve was used to estimate the discriminative ability of preoperative troponin for myocardial ischemia (MI). Results Of 105 patients with a mean age of 69.1 years, 32.4% had MI. Hypertension, diabetes mellitus, and dyslipidemia were the main risk factors. A ROC analysis indicated that a preoperative value of 17.2 pg/ml or higher of troponin was significantly associated with MI. Moreover, a higher CHA2DS2-VASc score was associated with POMI. Conclusions POMI is associated with high mortality and a long stay in the intensive care unit. Routine use of different scores before surgery can be very useful.

Nursing Workload in Patients With Myocardial Ischemia After Non-cardiac Surgery.

INTRODUCTION: Nursing workload (NWL) in the intensive care unit (ICU) is an essential parameter of patient safety. However, little attention has been dedicated to measuring NWL in ICU about patients surgically treated with myocardial ischemia (MI).  Methods: The objectives of this study are to describe and examine the NWL by applying the Nursing Activities Score in patients who underwent non-cardiac surgery and developed MI in the ICU. The statistical significance was set at 0.05. The statistical program SPSS 22.0 was used for the analysis. RESULTS:  The mean age was 69.1 years, whereas 32.4% of the patients had MI. Hypertension, diabetes mellitus, and dyslipidemia were the main comorbidities. On the first day in ICU, the NWL was similar in all patients (p = 0.947). In the following days, the NWL was significantly higher in patients with MI (p < 0.001). The NWL was considerably higher in patients with MI who died. CONCLUSIONS:  The present results are essential for planning and using nursing resources according to the care needs of postoperative patients with MI.

Erythropoetin as a novel agent with pleiotropic effects against acute lung injury.

Current pharmacotherapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is not optimal, and the biological and physiological complexity of these severe lung injury syndromes requires consideration of combined-agent treatments or agents with pleiotropic action. In this regard, exogenous erythropoietin (EPO) represents a possible candidate since a number of preclinical studies have revealed beneficial effects of EPO administration in various experimental models of ALI. Taken together, this treatment strategy is not a single mediator approach, but it rather provides protection by modulating multiple levels of early signaling pathways involved in apoptosis, inflammation, and peroxidation, potentially restoring overall homeostasis. Furthermore, EPO appears to confer vascular protection by promoting angiogenesis. However, only preliminary studies exist and more experimental and clinical studies are necessary to clarify the efficacy and potentially cytoprotective mechanisms of EPO action. In addition to the attempts to optimize the dose and timing of EPO administration, it would be of great value to minimize any potential toxicity, which is essential for EPO to fulfill its role as a potential candidate for the treatment of ALI in routine clinical practice. The present article reviews recent advances that have elucidated biological and biochemical activities of EPO that may be potentially applicable for ALI/ARDS management.

Nanomedicine: Photo-activated nanostructured titanium dioxide, as a promising anticancer agent.

The multivariate condition of cancer disease has been approached in various ways, by the scientific community. Recent studies focus on individualized treatments, minimizing the undesirable consequences of the conventional methods, but the development of an alternative effective therapeutic scheme remains to be held. Nanomedicine could provide a solution, filling this gap, exploiting the unique properties of innovative nanostructured materials. Nanostructured titanium dioxide (TiO2) has a variety of applications of daily routine and of advanced technology. Due to its biocompatibility, it has also a great number of biomedical applications. It is now clear that photo-excited TiO2 nanoparticles, induce generation of pairs of electrons and holes which react with water and oxygen to yield reactive oxygen species (ROS) that have been proven to damage cancer cells, triggering controlled cellular processes. The aim of this review is to provide insights into the field of nanomedicine and particularly into the wide context of TiO2-NP-mediated anticancer effect, shedding light on the achievements of nanotechnology and proposing this nanostructured material as a promising anticancer photosensitizer.

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution.

The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed "thymic involution." A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution.

A Recalcitrant Electrical Storm and Implantable Defibrillator Exhaustion: Treatment Implications According to and Beyond Guidelines.

A 60-year-old patient presented with recalcitrant electrical storm (ES). Mild sedation and initial antiarrhythmic combination of esmolol and amiodarone did not affect the intensity of ES, which resulted in battery exhaustion. Oral propranolol in addition to intravenous amiodarone might be preferred in hemodynamically stable patients before interventional therapies. (Level of Difficulty: Intermediate.).

The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies.

The genome is exposed daily to many deleterious factors. Ubiquitination is a mechanism that regulates several crucial cellular functions, allowing cells to react upon various stimuli in order to preserve their homeostasis. Ubiquitin ligases act as specific regulators and actively participate among others in the DNA damage response (DDR) network. UBE4B is a newly identified member of E3 ubiquitin ligases that appears to be overexpressed in several human neoplasms. The aim of this review is to provide insights into the role of UBE4B ubiquitin ligase in DDR and its association with p53 expression, shedding light particularly on the molecular mechanisms of carcinogenesis.

Mitochondrial Homeostasis and Cellular Senescence.

Cellular senescence refers to a stress response aiming to preserve cellular and, therefore, organismal homeostasis. Importantly, deregulation of mitochondrial homeostatic mechanisms, manifested as impaired mitochondrial biogenesis, metabolism and dynamics, has emerged as a hallmark of cellular senescence. On the other hand, impaired mitostasis has been suggested to induce cellular senescence. This review aims to provide an overview of homeostatic mechanisms operating within mitochondria and a comprehensive insight into the interplay between cellular senescence and mitochondrial dysfunction.

Senescence and senotherapeutics: a new field in cancer therapy.

Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life is linked with beneficial properties. In contrast, persistent (chronic) senescence seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due to the lack of a reliable marker able to detect senescence in vivo, its precise impact in age-related diseases is to a large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing senescence recognition in any type of biological material, emerges as a powerful tool to study the phenomenon of senescence in vivo. Exploiting the advantages of this novel methodological approach, scientists will be able to detect and connect senescence with aggressive behavior in human malignancies, such as tolerance to chemotherapy in classical Hodgkin Lymphoma and Langerhans Cell Histiocytosis. The latter depicts the importance of developing the new and rapidly expanding field of senotherapeutic agents targeting and driving to cell death senescent cells. We discuss in detail the current progress of this exciting area of senotherapeutics and suggest its future perspectives and applications.

A Novel Quantitative Method for the Detection of Lipofuscin, the Main By-Product of Cellular Senescence, in Fluids.

Lipofuscin accumulation is a hallmark of senescence. This nondegradable material aggregates in the cytoplasm of stressed or damaged cells due to metabolic imbalance associated with aging and age-related diseases. Indications of a soluble state of lipofuscin have also been provided, rendering the perspective of monitoring such processes via lipofuscin quantification in liquids intriguing. Therefore, the development of an accurate and reliable method is of paramount importance. Currently available assays are characterized by inherent pitfalls which demote their credibility. We herein describe a simple, highly specific and sensitive protocol for measuring lipofuscin levels in any type of liquid. The current method represents an evolution of a previously described assay, developed for in vitro and in vivo senescent cell recognition that exploits a newly synthesized Sudan Black-B analog (GL13). Analysis of human clinical samples with the modified protocol provided strong evidence of its usefulness for the exposure and surveillance of age-related conditions.

Correction to: A Novel Quantitative Method for the Detection of Lipofuscin, the Main By-Product of Cellular Senescence, in Fluids.

In Chapter 12, figure 1 was published with truncated texts within. This figure has now been replaced with a revised figure with the updated text.

Anakinra: an emerging option for refractory idiopathic recurrent pericarditis: a systematic review of published evidence.

AIMS: Accumulating evidence suggests idiopathic recurrent pericarditis as a disease of probable autoinflammatory origin, and thus anakinra could be of benefit. The goal of this systematic review was to assess the efficacy and safety of anakinra in this context. METHODS: Reports relevant to anakinra administration in patients with idiopathic recurrent pericarditis published up to October 2014 were searched in several databases. All references found, upon initial assessment at title and abstract level for suitability, were consequently retrieved as full reports for further appraisal. RESULTS: Among 12 citations retrieved, nine reports (four case series and five case reports with 34 patients, 20 men, mean age 26.8 years) were assessed. The mean disease duration was 31 months and the number of recurrences 8.2. Anakinra was generally administered as a daily subcutaneous injection of 100 mg or as a mean dose of 1.1 mg/kg/d in weight-adjusted regimens. The mean full-dose duration was 9.2 months. C-reactive protein normalized within 7.1 days, and steroids were withdrawn within 62 days. Dose tapering was adopted in 64.7% of patients, leading to recurrence in 26% of cases. In a 28.3-month follow-up, eight out of 34 patients (23.5%) were disease free without treatment, after having received anakinra for 10.4 months overall. Anakinra was proved well tolerated, with mild local reaction being reported in 44% of patients. CONCLUSION: Anakinra is a highly effective, rapidly acting, well tolerated and steroid-sparing agent. Recurrences after drug discontinuation are a matter of concern. Randomized trials are required to confirm these findings and address the most effective treatment protocol.