Istituto Nazionale per le Ricerche Cardiovascolari

Abstract Objective Transfer RNA-derived fragments (tRFs) belong to an emerging class of small non-coding RNAs that dynamically respond to metabolic stressors and drive different pathological processes, yet their role in osteoarthritis (OA) remains poorly explored. We aimed to define the tRF landscape in OA and investigate the function of 3’tRF Asp(GTC) in chondrocyte stress adaptation and translational control. Methods Ex vivo , cartilage specimens from OA patients (n=6) and healthy donors (n=7) were analyzed by small RNA sequencing to define disease-associated tRF signatures. In vitro , primary chondrocytes derived from OA patients were treated with lipopolysaccharide (LPS) to mimic inflammatory environment of OA, used for small RNA sequencing (n=3) and validation analysis (n=6). Functional studies in C28/I2 chondrocytes included antisense oligonucleotide-mediated 3’tRF Asp(GTC) inhibition, AGO2-RNA immunoprecipitation (RIP), polysome profiling, stress granule (SG) immunofluorescence, and differential protein analysis. Computational target prediction and pathway enrichment were used to explore tRF-mediated regulatory networks. Results Both OA cartilage and LPS-treated chondrocytes displayed upregulation of 3’tRF Asp(GTC) and 5’tRF Glu(CTC) , indicating a shared inflammatory tRF signature. Predicted targets of upregulated tRFs were enriched in stress-adaptive, proteostasis, and translational control pathways, whereas downregulated tRFs modulated mitochondrial processes. Silencing 3’tRF Asp(GTC) inhibited LPS-induced COX2 and MMP13 expression, prevented ER stress, and blocked SG assembly. RIP confirmed selective recruitment of 3’tRF Asp(GTC) into AGO2 complexes. Polysome profiling revealed association with 40S ribosomal subunit, mediating translational arrest and influencing selective mRNA expression. Conclusion 3’tRF Asp(GTC) emerges as a regulator linking inflammation to translational control and SG dynamics in OA. tRFs thus could represent novel therapeutic targets in OA disease.

We read with great interest the study by Peng et al. on the mortality and survival analysis in patients with cancer occurrence after Sjögren's syndrome (SS-CA), which provides valuable insights into the long-term prognosis of this vulnerable population [1]. Their findings underscore the significant impact of malignancy on survival outcomes in patients with SS, with a standard mortality ratio (SMR) of 2.61 and markedly reduced overall survival compared to controls. Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and diverse extraglandular manifestations [2]. The chronic inflammatory milieu and persistent immune activation in SS contribute not only to organ damage, such as renal involvement [3], but also to an increased risk of hematologic malignancies, particularly non-Hodgkin lymphoma. This has been well recognized and remains one of the most severe complications in the disease course [4]. Peng et al.'s demonstration that a short interval between SS diagnosis and cancer onset (≤ 3 years) and the presence of hematological malignancies are strong predictors of poor survival aligns with previous knowledge regarding the pathophysiological burden of uncontrolled lymphoproliferation in SS [2, 5]. It is also worth noting that the age at SS diagnosis may not reflect the true onset of the disease, as many patients experience sicca syndrome symptoms for years prior to receiving a formal diagnosis. This diagnostic delay complicates both clinical management and trial design, especially when attempting to define early disease. Age at SS diagnosis above 50 years, identified as another independent predictor of worse prognosis, suggests that early disease recognition and monitoring for malignancy are essential, especially in older patients. Moreover, pulmonary complications, including pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), have been increasingly reported in SS patients, contributing to overall morbidity and mortality [6]. Recently, consensus guidelines for the evaluation and management of pulmonary disease in Sjögren's syndrome have been published, offering structured recommendations for diagnosis and follow-up. Future studies will need to assess whether the implementation of these guidelines improves outcomes in real-world clinical practice [7]. Cardiovascular risk factors and PAH, in particular, might act synergistically with cancer to further worsen outcomes [8]. The association between PAH and a higher risk of death in autoimmune diseases, such as SS, points to the need for comprehensive cardiovascular evaluation in these patients [9]. Another important point to consider is the variability of clinical manifestations and the heterogeneity of SS presentations across different populations, as evidenced by prior studies on the prevalence of sicca syndrome symptoms and secondary SS in rheumatoid arthritis patients. Although several algorithms have been developed to predict lymphoma risk based on clinical and serological features, there is currently no validated tool to assess cancer risk more broadly in patients with SS. Such variability might influence the risk and type of malignancy and needs to be factored into individualized risk assessments [5-10]. In conclusion, Peng et al.'s study highlights the importance of vigilance in monitoring SS patients for early signs of malignancy, particularly within the first 3 years after SS diagnosis. A multidisciplinary approach, incorporating rheumatology, oncology, and cardiology expertise, is paramount for optimizing outcomes in this complex patient population. All authors contributed equally to this work. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognized cause of acute coronary syndrome, primarily affecting young women without traditional cardiovascular risk factors. We report the case of a 57-year-old woman with obesity and a history of smoking, admitted for acute respiratory failure due to pneumonia, complicated by cardiac arrest. Elevated troponin levels, along with subsequent ECG and echocardiographic findings suggestive of previous myocardial ischemia, led to the indication for coronary angiography. The angiogram revealed severe three-vessel coronary disease with three distinct SCADs involving the left anterior descending, right coronary, and circumflex arteries. Advanced imaging, including whole-body positron emission tomography, revealed active systemic vasculitis. A multidisciplinary approach led to initiation of immunosuppressive therapy with corticosteroids and tocilizumab, alongside conservative cardiac management with dual antiplatelet therapy. At 1-year follow-up, the patient showed significant improvement in left ventricular function and normalization of inflammatory markers. This case highlights the diagnostic and therapeutic complexity of multiple SCADs, particularly in the context of underlying systemic inflammatory diseases, and underscores the importance of individualized treatment strategies and multidisciplinary collaboration.

Timely myocardial reperfusion is essential for restoring blood flow to post-ischemic tissue, thereby reducing cardiac injury and limiting infarct size. However, this process can paradoxically result in additional, irreversible myocardial damage, known as myocardial ischemia-reperfusion injury (MIRI). The goal of this review is to explore the role of specialized pro-resolving mediators (SPMs) in atherosclerosis and MIRI, and to assess the therapeutic potential of targeting inflammation resolution in these cardiovascular conditions. This review summarizes current preclinical and clinical evidence on the involvement of SPMs in the pathogenesis of atherosclerosis and MIRI, acknowledging that several cellular and molecular aspects of their mechanisms of action remain to be fully elucidated. MIRI is a complex phenomenon in which inflammation, initially triggered during ischemia and further amplified upon reperfusion, plays a central role in its pathogenesis. Various cellular and molecular players mediate the initial pro-inflammatory response and the subsequent anti-inflammatory reparative phase following acute myocardial infarction (AMI), contributing both to ischemia- and reperfusion-induced damage as well as to the healing process. SPMs have emerged as key endogenous immunoresolvents with potent anti-inflammatory, antioxidant, and pro-resolving properties that contribute to limit excessive acute inflammation and promote tissue repair. While dysregulated SPM-related signaling has been linked to various cardiovascular diseases (CVD), their precise role in AMI and MIRI remains incompletely understood. Targeting inflammation resolution may represent a promising therapeutic strategy for mitigating atheroprogression and addressing a complex condition such as MIRI.

BackgroundSeveral factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both in vitro and ex vivo. MethodsTo investigate the relationship between NLRP3 and myocardial IRI, we synthetized a series of novel NLRP3 inhibitors, and investigated their putative binding mode via docking studies. Through in vitro studies we identified INF195 as optimal for NLRP3 inhibition. We measured infarct-size in isolated mouse hearts subjected to 30-min global ischemia/one-hour reperfusion in the presence of three different doses of INF195 (5, 10, or 20-μM). We analyzed caspase-1 and IL-1β concentration in cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed by Tukey's test. Results and conclusionINF195 reduces NLRP3-induced pyroptosis in human macrophages. Heart pre-treatment with 5 and 10-μM INF195 significantly reduces both infarct size and IL-1β levels. Data suggest that intracardiac NLRP3 activation contributes to IRI and that low doses of INF195 exert cardioprotective effects by reducing infarct size. However, at 20-μM, INF195 efficacy declines, leading to a lack of cardioprotection. Research is required to determine if high doses of INF195 have off-target effects or dual roles, potentially eliminating both harmful and cardioprotective functions of NLRP3. Our findings highlight the potential of a new chemical scaffold, amenable to further optimization, to provide NLRP3 inhibition and cardioprotection in the ischemia/reperfusion setting.

Maladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute cardiac protection. However, its action in chronic settings of cardiac dysfunction is not understood. Here, we investigated the role of SELENOT in the pathophysiology of HF: (i) by designing a small peptide (PSELT), recapitulating SELENOT activity via the redox site, and assessed its beneficial action in a preclinical model of HF [aged spontaneously hypertensive heart failure (SHHF) rats] and against isoproterenol (ISO)-induced hypertrophy in rat ventricular H9c2 and adult human AC16 cardiomyocytes; (ii) by evaluating the SELENOT intra-cardiomyocyte production and secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, and the severe ultrastructural alterations, while counteracting key mediators of cardiac fibrosis, aging, and DNA damage and restoring desmin downregulation and SELENOT upregulation in the failing hearts. In the hemodynamic assessment, PSELT improved the contractile impairment at baseline and following ischemia/reperfusion injury, and reduced infarct size in normal and failing hearts. At cellular level, PSELT counteracted ISO-mediated hypertrophy and ultrastructural alterations through its redox motif, while mitigating ISO-triggered SELENOT intracellular production and secretion, a phenomenon that presumably reflects the extent of cell damage. Altogether, these results indicate that SELENOT could represent a novel sensor of hypertrophied cardiomyocytes and a potential PSELT-based new therapeutic approach in myocardial hypertrophy and HF.Graphical

The prevention of cardiovascular diseases is a fundamental pillar for reducing morbidity and mortality caused by non-communicable diseases. Social determinants, such as socioeconomic status, education, neighborhood, physical environment, employment, social support networks, and access to health care, play a crucial role in influencing health outcomes and health inequities within populations. Social determinants and stress in women are interconnected factors that can significantly impact women's health and well-being. Pregnancy is a good time to engage young women and introduce them to beneficial behaviors, such as adopting essential life skills, especially diet, and learning stress management techniques. Stress influences diet, and women are more likely to engage in unhealthy eating behaviors such as emotional eating or coping with stress with food. Strong action is needed to improve women's lifestyle starting at a young age considering that this lays the foundation for a lower cardiovascular risk in adults and the elderly. The objective of this review is to examine cardiovascular primary prevention in young healthy women, focusing particularly on unresolved issues and the influence of social determinants, as well as the correlation with stressors and their influence on diet.

Congestion is the main therapeutic target of acute heart failure (HF) treatment, and loop diuretics (LDs) are widely used drugs for this purpose. Despite their extensive use, these agents remain largely understudied in terms of modality administration, treatment duration, and escalation dose for subjects responding poorly to therapy. LDs were initially investigated in several edematous statuses such as cirrhosis, nephrotic syndrome, and congestive HF and initially approved for the treatment of cardiogenic congestion in 1966. Despite the long history and the undoubted role in congestion management, the use of LDs in the acute phase is mostly based on the physician’s experience, the oral amount chronically administered, and clinical decongestion response. Recent literature suggests monitoring diuretic activity by the evaluation of daily diuresis, weight loss, and sample urinary sodium assessment after early intravenous LD administration. More recently, the measurement of urinary sodium integrated with urinary and blood creatinine values and fluid status has been suggested as optimal marker to predict whole diuretic efficiency and to target the optimal dose. However, this method is not easily available in the chronic setting or in patients with recurrent hospitalization taking a high loop diuretic amount. Since high loop diuretic dose is related to diuretic resistance (DR) and poorer outcome, additional diuretics acting in different nephron sites are often required. Current sequential nephron blockade can stimulate diuresis by synergic mechanisms. This strategy is attempted in patients with poor response, revealing good results in the early period, but the effects of neuro-endocrine stimulation and electrolyte balance across long-term follow-up are still questioned. This paper reviews the historical course of loop diuretics and highlights the need for a universal approach based on clinical conditions, cardio–renal interactions, and HF phenotypes.

Vitamin D3 (VitD3) plays a crucial role in various cellular functions through its receptor interaction. The biological activity of Vitamin D3 can vary based on its solubility and stability. Thus, the challenge lies in maximizing its biological effects through its complexation within cyclodextrin (βNS-CDI 1:4) nanosponges (NS) (defined as VitD3NS). Therefore, its activity has been evaluated on two different gut-brain axes (healthy gut/degenerative brain and inflammatory bowel syndrome gut/degenerative brain axis). At the gut level, VitD3-NS mitigated liposaccharide-induced damage (100 ng/mL; for 48 h), restoring viability, integrity, and activity of tight junctions and reducing ROS production, lipid peroxidation, and cytokines levels. Following intestinal transit, VitD3-NS improved the neurodegenerative condition in the healthy axis and the IBS model, suggesting the ability of VitD3-NS to preserve efficacy and beneficial effects even in IBS conditions. In conclusion, this study demonstrates the ability of this novel form of VitD3, named VitD3-NS, to act on the gut-brain axis in healthy and damaged conditions, emphasizing enhanced biological activity through VitD3 complexation, as such complexation increases the beneficial effect of vitamin D3 in both the gut and brain by about 50%.

The development and use of messenger RNA-based (mRNA) vaccines against the SARS-CoV-2 spike protein have proven to be highly effective against symptomatic COVID-19, especially for severe forms. Since the declaration of a public health emergency in early 2020, however, the SARS-CoV-2 virus has continuously evolved, giving rise to several variants that have caused and continue to cause concern in the scientific community. Currently, viruses circulating worldwide belong to the Omicron lineage, with several identified sub-variants. In response to virus mutation, mRNA vaccines have been adapted into bivalent vaccines containing two mRNAs: one encoding the original Wuhan SARS-CoV-2 spike protein and one encoding the BA.1 or BA.4-5 spike protein of the Omicron sub-variant. This strategy is based on the hypothesis that the immune system's response improves when variants are included in the vaccine, leading to an increase in the magnitude and diversity of both the humoral and cellular immune response. The evidence gathered to date confirms the use of bivalent vaccines as the optimal strategy. In the light of current knowledge, and in the awareness of the impossibility of making precise predictions on the evolution of the COVID-19 pandemic, as a group of experts we propose some considerations for the progressive evolution of vaccination against SARS-CoV-2 from pandemic to endemic vaccination.