BACKGROUND: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect.
METHODS: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction.
RESULTS: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients\' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF.
CONCLUSIONS: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.

In this experiment, we studied a rodent model selected over 57 generations for high or low rates of ultrasonic vocalizations (USVs) during maternal separation as pups. We investigated the influence of this breeding on the adult animals\' subsequent vocal output, comparing acoustic variables across developmental stages. We hypothesized that selection on pup USV rate would impact adult USV production without affecting lower frequency calls. Contrary to this hypothesis, we found neither number of USV calls or other acoustic variables to differ among selected adult lines. Instead, we found that pup USV selection mainly affected adults\' low-frequency (human-audible) calls. Furthermore, low-frequency vocalizations did not fully fit a predicted correlation between body weight and fundamental frequency: high line males, although the heaviest on average, did not produce the lowest fundamental frequencies. Our findings suggest that selection for early ultrasonic vocal behaviour pleiotropically results in changes in anatomical production mechanisms and/or neural control affecting low-frequency calls.

Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment.

Heart rate (HR) lowering during acute coronary syndrome (ACS) is beneficial as it reduces myocardial oxygen consumption. However, the role of ivabradine as an HR-lowering agent in the setting of ACS is not clear. We aimed to systematically review and synthesize the current evidence on the role of ivabradine use in the ACS. A systematic review was conducted for eligible randomized clinical trials and quasi-experimental studies, between 2009 and 2020, that investigated the use of ivabradine in ACS. Various clinical endpoints were evaluated such as major adverse cardiovascular events, efficacy in HR control, impact on left ventricular (LV) dimensions and function, and overall safety. Eleven publications were included encompassing a total of 1833 patients. The mean age of the examined cohort was 57 ± 11 years and 80 % were men. Seven studies were in the setting of ST-segment elevation myocardial infarction (MI) while the remaining studies also included patients with unstable angina and non-ST-segment elevation MI. Ivabradine was administered as a peroral drug with dosing from 2.5 to 7.5 mg b.i.d. Overall, the addition of ivabradine was superior to the control arm concerning HR control with a good safety profile. Beneficial effects on LV function and potential impact on infarct size reduction were observed as well. The use of ivabradine appeared to not affect short-term mortality. In conclusion, the use of ivabradine for HR control is safe, feasible, and efficacious for HR control in the ACS. Further studies are required to elucidate other potentially beneficial effects of ivabradine.

Melatonin is a ubiquitous regulator in plants and performs a variety of physiological roles, including resistance to abiotic stress, regulation of growth and development, and enhancement of plant immunity. Melatonin exhibits the characteristics of a phytohormone with its pleiotropic effects, biosynthesis, conjugation, catabolism, effective concentration, and the shape and location of its dose-response curves. In addition, CAND2/PMTR1, a phytomelatonin receptor candidate belonging to the G protein-coupled receptors (GPCRs), supports the concept of melatonin as a phytohormone. However, the biochemistry of plant melatonin receptors needs to be further characterized. In particular, some of the experimental findings to date cannot be explained by known GPCR signaling mechanisms, so further studies are needed to explore the possibility of novel signaling mechanisms.

This review provides a comprehensive exploration of the intricate relationship between statins and stroke prevention within the broader context of cardiovascular health. Delving into the mechanisms of statins, we elucidate their multifaceted contributions, ranging from cholesterol reduction to pleiotropic effects on the vascular system. Through a meticulous analysis of clinical trials, observational studies, and mechanistic investigations, we underscore the pivotal role of statins as integral components in the arsenal against strokes and associated cardiovascular events. The implications extend beyond statins as standalone interventions, emphasizing the potential for synergistic integration into broader stroke prevention strategies. Tailoring interventions to individual patient profiles and understanding the interplay with lifestyle modifications and other pharmacological approaches present opportunities for optimizing efficacy. Recommendations for future research advocate for continued exploration into the long-term effects of statin therapy, novel intervention combinations, and refined predictive models for personalized risk assessment. On a practical level, enhancing patient education, fostering interdisciplinary collaboration, and addressing barriers to medication adherence emerge as crucial aspects for real-world impact. In navigating this evolving landscape, the insights derived from this review contribute to informed decision-making and advancements in preventive cardiovascular medicine.

HMG-CoA reductase inhibitors, commonly known as statins, are the primary treatment choice for cardiovascular diseases, which stand as the leading global cause of mortality. Statins also offer various pleiotropic effects, including improved endothelial function, anti-inflammatory properties, reduced oxidative stress, anti-thrombotic effects, and the stabilization of atherosclerotic plaques. However, the usage of statins can be accompanied by a range of adverse effects, such as the development of type 2 diabetes mellitus, muscular symptoms, liver toxicity, kidney diseases, cataracts, hemorrhagic strokes, and psychiatric complications. These issues are referred to as statin-associated symptoms (SAS) and are relatively infrequent in clinical trials, making it challenging to attribute them to statin use definitively. Therefore, these symptoms can lead to significant problems, necessitating dose adjustments or discontinuation of statin therapy. This review aims to provide a comprehensive overview of the mechanism of action, potential advantages, and associated risks of statin utilization in clinical settings.

Direct Oral Anticoagulants (DOACs) have simplified the treatment of thromboembolic disease. In addition to their established anticoagulant effects, there are indications from clinical and preclinical studies that DOACs exhibit also non-anticoagulant actions, such as anti-inflammatory and anti-oxidant actions, advocating overall cardiovascular protection. In the present study, we provide a comprehensive overview of the existing knowledge on the pleiotropic effects of DOACs on endothelial cells (ECs) in vitro and their underlying mechanisms, while also identifying potential differences among DOACs. DOACs exhibit pleiotropic actions on ECs, such as anti-inflammatory, anti-atherosclerotic, and anti-fibrotic effects, as well as preservation of endothelial integrity. These effects appear to be mediated through inhibition of the proteinase-activated receptor signaling pathway. Furthermore, we discuss the potential differences among the four drugs in this class. Further research is needed to fully understand the pleiotropic effects of DOACs on ECs, their underlying mechanisms, as well as the heterogeneity between various DOACs. Such studies can pave the way for identifying biomarkers that can help personalize pharmacotherapy with this valuable class of drugs.

Influenza vaccines are designed to mimic natural influenza virus exposure and stimulate a long-lasting immune response to future infections. The evolving nature of the influenza virus makes vaccination an important and efficacious strategy to reduce healthcare-related complications of influenza. Several lines of evidence indicate that influenza vaccination may induce nonspecific effects, also referred to as heterologous or pleiotropic effects, that go beyond protection against infection. Different explanations are proposed, including the upregulation and downregulation of cytokines and epigenetic reprogramming in monocytes and natural killer cells, imprinting an immunological memory in the innate immune system, a phenomenon termed \"trained immunity\". Also, cross-reactivity between related stimuli and bystander activation, which entails activation of B and T lymphocytes without specific recognition of antigens, may play a role. In this review, we will discuss the possible nonspecific effects of influenza vaccination in cardiovascular disease, type 1 diabetes, cancer, and Alzheimer\'s disease, future research questions, and potential implications. A discussion of the potential effects on infections by other pathogens is beyond the scope of this review.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.