European Journal of Clinical Investigation

Background Diabetes of the exocrine pancreas (DEP) is an underdiagnosed form of diabetes, prevalently caused by acute and chronic pancreatitis (CP). The contribution of incretin system dysfunction and the role of glucagon levels in the pathogenesis of DEP remain unclear. The aim of our study is to assess the secretion of glucagon like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic peptide (GIP) and glucagon, along with the incretin effect, in individuals with and without CP. By comparing these parameters within the same glucose tolerance class, we seek to elucidate specific hormonal alterations that characterize DEP. Methods To pursue this aim, we conducted a cross‐sectional study on 32 patients with chronic pancreatitis (wCP) and 60 patients without chronic pancreatitis (w/oCP), who were administered an oral glucose tolerance test, a hyperglycemic clamp and a mixed meal test with measurement of glucose, insulin, C‐peptide, GLP‐1, GIP and glucagon. Results The comparison between individuals wCP and w/oCP showed worse beta‐cell function and lower incretin effect for the former, but incretin and glucagon levels were similar. Diabetes prevalence was higher in the group wCP than in the group w/oCP (56% vs. 33%). Thus, to evaluate the differences determined by CP, we found it necessary to stratify individuals according to glucose tolerance class. After stratification, we found that both groups had similar beta‐cell function, incretin effect and incretin and glucagon secretion. Conclusions Therefore, incretin and glucagon levels and the incretin effect varied according to glucose tolerance, not the presence or absence of CP. Similar defects in incretin secretion and effects are responsible for diabetes development in individuals wCP and w/oCP.

Background Atrial fibrillation (AF) is associated with a prothrombotic state. We investigated whether factor VIIa‐antithrombin (FVIIa‐AT) complexes, a marker of tissue factor (TF) exposure, are associated with thromboembolic events in AF. Methods In 224 nonvalvular AF patients (66% men, median age 69 years, median CHA2DS2VASc score 4), 71% on direct oral anticoagulants, we measured FVIIa‐AT complexes, along with endogenous thrombin potential (ETP), von Willebrand factor (VWF) and 8‐isoprostane, reflecting oxidative stress. During a median follow‐up of 53 [interquartile range, IQR 47–57] months, we recorded a composite endpoint: ischemic stroke, systemic thromboembolism or cardiovascular (CV) death. Results FVIIa‐AT complexes (median 145 [IQR 125–170] pM) were higher in patients with permanent AF (p < .001), vascular disease (p = .02), previous stroke (p < .001) and smoking (p = .006) as compared with patients without these comorbidities. FVIIa‐AT correlated with NT‐proBNP (r = .15, p = .022) and ETP (r = .25, p < .001). During follow‐up, the composite endpoint was recorded in 30 patients (13.4%, 3.0% per year) including 20 with ischemic stroke (8.9%, 2.0% per year, respectively). Patients with the composite endpoint had 29.2% higher baseline FVIIa‐AT complexes compared with the remainder. Patients with FVIIa‐AT complexes in the top quartile (>170 pM) had an increased risk of the composite endpoint (HR 12.0, 95% CI 5.2–28.0, p < .0001). FVIIa‐AT complexes, along with VWF, remained independently associated with the composite endpoint. Conclusions This study is the first to show that high plasma FVIIa‐AT complexes are independently associated with thromboembolic events or CV death in AF, suggesting the need for more potent anticoagulation to suppress the residual TF‐mediated coagulation.

Background Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found to reflect systemic mitochondrial fitness and bioenergetic health. We sought to identify bioenergetic differences in PBMCs and platelets from children with obesity and insulin resistance and determine associations with whole‐body metabolism and/or biomarkers of metabolic health and inflammation. Methods We stratified prepubertal children (ages 5–10 years) into three groups: normal weight insulin sensitive (N‐IS; n = 20), overweight/obese insulin sensitive (O‐IS; n = 28) and overweight/obese insulin resistant (O‐IR; n = 17). We measured oxygen consumption rate and proton efflux rate in PBMCs and platelets. We estimated whole‐body resting metabolic rate by bioimpedance and dietary fatty acid oxidation by oral deuterated palmitate and quantifying recovery of D2O in urine. We used ANOVA for comparisons among groups and Spearman correlations for associations between circulating cell bioenergetics and whole‐body metabolism and biomarkers. Results O‐IS and O‐IR PBMCs exhibited increased maximal mitochondrial respiration and spare respiratory capacity compared to N‐IS. Bioenergetics shifted towards glycolysis in O‐IS PBMCs as compared to both N‐IS and O‐IR PBMCs. In platelets, glycolysis and ATP production rates were decreased in O‐IR compared to O‐IS children. PBMC respiration positively correlated with BMIz, HOMA‐IR and fasting glucose and insulin, but negatively correlated with inflammatory cytokines. Dietary fatty acid oxidation was higher in O‐IS compared to N‐IS children and positively correlated with PBMC spare respiratory capacity. Resting metabolic rate correlated positively with several parameters of PBMC mitochondrial respiration. Conclusions PBMCs from young children with overweight/obesity exhibit adaptations to the metabolic stressors associated with insulin resistance, and PBMC metabolism correlates well with whole‐body metabolism.

Background The increasing prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as non‐alcoholic fatty liver disease (NAFLD), represents a significant public health concern, as it is closely linked to rising obesity rates and metabolic syndrome, affecting approximately 30% of the global population. In addition, MASLD, along with its more severe form, metabolic dysfunction‐associated steatohepatitis (MASH), increases the risk of cardio‐metabolic diseases and hepatocellular carcinoma. In recent years, multiple G‐protein‐coupled receptors (GPCRs) have been identified as potential therapeutic targets for these disorders. Additionally, autoimmunity is believed to potentially play a role in the development of mechanisms contributing to the pathogenesis of MASLD/MASH. This narrative review examines the diverse autoantibodies associated with the disease, with a particular emphasis on antibodies targeting apolipoprotein A‐1 (AAA‐1) and their relationship with anti‐GPCRs antibodies. Results Several autoantibodies have been identified in up to 30% of individuals with MASLD/MASH, both with and without concomitant autoimmune diseases. Among the anti‐GPCR autoantibodies identified in MASLD to date are those targeting the angiotensin II type 1 receptor and the endothelin‐1 type A receptor. While the contribution of this class of autoantibodies to MASLD/NASH remains unclear, AAA‐1 appears to be pathogenic, acting as pro‐steatotic and pro‐inflammatory mediators. Additionally, current data suggest shared functional responses between anti‐GPCR antibodies and AAA1 in cell‐based assays used to detect anti‐GPCR presence. Conclusion A better understanding of the role of humoral autoimmunity and the interactions among its various components in the metabolic dysfunction underlying MASLD/MASH has the potential to open new perspectives for early detection and therapeutic interventions.

Background Sex and gender are fundamental determinants of health, influencing disease risk, diagnosis, treatment, and outcomes across medical disciplines. While sex refers to biological characteristics, gender encompasses sociocultural dimensions, including behaviours and identities. Results The field of gender medicine has evolved significantly from its roots in the women's health movement of the 1960s and 1970s, which initially sought to address reproductive rights and the systematic exclusion of women from clinical research. Over time, the focus has expanded to recognize sex‐ and gender‐based differences in all populations, including men and gender‐diverse individuals. Despite progress, persistent challenges remain. Many clinical guidelines inadequately incorporate sex and gender considerations, and women continue to be underrepresented in clinical trials, resulting in suboptimal efficacy and a higher incidence of adverse effects in women. Recent initiatives, including government‐funded research programs, specialized gender medicine professorships and regulatory measures promoting equitable clinical trial participation, represent positive steps forward. However, a systematic, interdisciplinary approach is required to fully integrate gender‐sensitive medicine into research, education and clinical practice. This narrative review explores the historical development of gender medicine, current advancements and remaining challenges. We highlight the need for improved research methodologies, policy changes and targeted interventions to ensure equitable healthcare. A structured action plan emphasizing regulatory support, education, industry involvement and public awareness is essential to accelerate the field's integration. Conclusion Recognising and addressing sex‐ and gender‐sensitive health differences will lead to more personalised and effective medical care, ultimately improving health outcomes for all individuals.

Background Chronic kidney disease (CKD) significantly impacts patient well‐being, with declining glomerular filtration rate (eGFR) often leading to worsening quality of life (QoL). However, the directionality of the eGFR–QoL relationship remains unclear due to limitations of prior cross‐sectional and longitudinal studies. Methods This study applied cross‐lagged analysis to investigate the reciprocal relationship between eGFR and QoL (measured using SF‐36 Physical and Mental Component Scores [PCS and MCS]) over 36 months in 422 CKD patients recruited from nephrology units in Southern Italy. Generalized Method of Moments (GMM) models tested two hypotheses: (1) PCS as a determinant of MCS, or vice versa; and (2) eGFR as a determinant of MCS/PCS, or vice versa. Results Cross‐lagged analysis confirmed that lower eGFR significantly predicted declines in both PCS and MCS in subsequent visits (p < .05). At the same time, the reverse relationship (QoL affecting eGFR) was not statistically significant. Multivariable models, adjusting for potential confounders including demographic factors, comorbidities, and socioeconomic status, confirmed these findings. Conclusion Kidney function decline leads to worsening QoL, whereas deterioration in QoL does not impact eGFR decline. These findings support prioritising interventions that slow the progression of CKD as a means to preserve quality of life. This study highlights the utility of cross‐lagged analysis in nephrology research and underscores the importance of early chronic kidney disease (CKD) management to maintain patient well‐being.

Background Clinical associations and prognosis of patients with symptom‐controlled AF (scAF) remain poorly understood. Methods We analysed data from the Asian‐Pacific Heart Rhythm Society and EURObservational Research Programme registries. Based on the European Heart Rhythm Association (EHRA) score, patients were classified as scAF (EHRA I or II) or symptomatic AF (EHRA III or IV). Clinical characteristics were examined by logistic regression, and prognosis was assessed by Cox models. The primary outcome was composed of all‐cause death and major cardiovascular events. Interaction analyses were performed to investigate ethnic differences. Results Among 13,577 AF patients (mean age 69.0 ± 11.6 years; 38.7% female), 11,470 (84.5%) had scAF. Asians were more likely to be scAF, characterised by younger age and lower cardiovascular burden compared to Europeans. Diabetes mellitus was significantly associated with scAF only in Asians (adjusted odd ratio [aOR] 1.43, 95% confidence interval [CI] 1.03–2.04, pinteraction = 0.021). The associations with hypertension (aOR 1.29, 95% CI 0.98–1.70, pinteraction = 0.004) and prior ischemic stroke (aOR 1.75, 95% CI 0.96–3.58, pinteraction = 0.045) were more evident in Asians. Patients with scAF showed a notable association with increased likelihood of using vitamin K antagonists (aOR 1.19, 95% CI 1.07–1.33), which was more prominent in Asians. In both Asians and Europeans, scAF was associated with reduced rhythm control management. Compared to non‐scAF, European patients with scAF had a reduced risk of the composite outcome, but the association was non‐significant in Asians (pinteraction = 0.594). Conclusion Asians and Europeans with scAF demonstrate clinically relevant differences in terms of overall prevalence, related risk factors, and clinical management.

Background The role of the gastric microbiome in the pathophysiology of gastritis beyond Helicobacter pylori (HP) infection is poorly understood and has remained unexplored in patients with obesity. The aim of this study was to analyse gastric mucosa‐associated microbiota in patients with obesity and nonatrophic chronic gastritis in the absence of HP infection or history of HP eradication. Methods This was a case–control study conducted at Virgen de la Victoria University Hospital in Malaga, performed in patients with severe obesity (body mass index ≥40 kg/m²) undergoing sleeve gastrectomy, without HP infection and no history of HP eradication. Gastric biopsy specimens were collected at surgery and were analysed by 16S rRNA sequencing. Participants were divided into two groups according to the histological evaluation: nonatrophic chronic gastritis and nongastritis. An exploratory prospective analysis to determine the influence of gastritis on short‐term outcomes after surgery was also performed. Results Sixty‐seven participants (38 in the gastritis and 29 in the nongastritis group) were included. A lower alpha diversity (evenness and Shannon diversity indexes) and beta diversity (weighted Unifrac distance) were shown in the gastritis group. Higher relative abundances in the families Micrococcaceae, Streptococcaceae and Leuconostocaceae and the genera Streptococcus, Weissella and Cryptobacterium were observed in the gastritis group, compared with the nongastritis group. An enrichment in pathways involved in toluene degradation, heterolactic fermentation and secondary metabolites biosynthesis, such as ergothioneine and terpenoids, was found in the gastritis group. Also, higher total cholesterol levels 1 year after the surgery were observed in the gastritis group compared with the nongastritis group, although no within‐group differences from baseline to 1 year were detected in this parameter. Conclusion Our results suggest a relationship between the gastric microbiome and nonatrophic chronic gastritis in obesity, beyond HP infection.

Background Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is associated with a significantly increased risk of mortality and morbidity from stroke, thromboembolism and dementia. Recent advances in stroke prevention strategies necessitate an updated approach to management. Results Published evidence shows that the Atrial Fibrillation Better Care (ABC) pathway significantly improves stroke prevention outcomes in AF patients, reducing mortality, stroke incidence and bleeding events. Characterisation of AF using the 4S‐AF framework helped guide personalised treatment selection and was associated with improved clinical outcomes. For patients unsuitable for anticoagulation, left atrial appendage occlusion has been identified as a viable alternative. Digital health technologies demonstrate increasing utility in early AF detection to enable timely stroke prevention interventions. There is evidence for the dynamic nature of stroke (and bleeding) risk, as well as arrhythmia burden and AF progression over time, in addition to changes in ABC pathway adherence. Conclusions Effective stroke prevention in AF requires a comprehensive holistic approach incorporating appropriate risk stratification, guideline‐adherent anticoagulation and management of underlying cardiovascular conditions and other comorbidities. The ABC pathway, supported by characterisation using the 4S‐AF framework, provides a structured approach to optimise outcomes. Regular reassessment of risk, along with careful selection of anticoagulation strategies, remains crucial. Integration of digital health technologies and structured care pathways shows promise in improving patient outcomes.

Background This study evaluated whether plasma PCSK9 is associated with coronary plaque progression in patients with coronary artery disease (CAD) and assessed its involvement in molecular processes of atherogenesis. Methods Plasma PCSK9 was measured in 159 patients with stable CAD submitted to coronary computed tomography angiography (CTA) at baseline and after a follow‐up of 6.5 ± 1.1 years. Plaque progression was defined as the annual increase in Total, Fibrous, Fibro‐fatty, Necrotic‐Core and Dense‐Calcium plaque volumes (PV). Pathways linked with PCSK9 were studied by RNA‐sequencing of whole blood and in vitro studies using endothelial cells (EC). Results At multivariable analysis, plasma PCSK9 was associated with an annual increase in Necrotic‐Core PV (p = .022) independent of cardiovascular risk factors, molecular markers, and medications, including LDL‐C and statins. At RNA‐seq analysis, PCSK9 was linked to the expression of genes involved in the innate‐immune response. Treating EC with PCSK9 resulted in a significant increase in ICAM‐1, VCAM‐1, MCP1 and IL6 mRNA expression. Conclusions In patients with CAD, plasma PCSK9 is associated with progression of Necrotic Core‐PV. The link with inflammatory pathways suggested for PCSK9 a potential role for the occurrence of prognostically adverse plaque phenotypes beyond LDL‐C regulation.

Background The benefits of sodium‐glucose cotransporter 2 inhibitors (SGLT2is) versus dipeptidyl peptidase‐4 inhibitors (DPP4is) in type 2 diabetes people with varying acute kidney injury (AKI) intervals or recovery remain unclear. Methods We retrospectively analysed 3127 paired patients with a prior history of AKI within 60 months before drug initiation, who received either SGLT2i or DPP4i between June 2016 and December 2021, utilizing 1:1 propensity score matching to balance baseline characteristics. AKI was defined as a serum creatinine (sCr) increase of ≥50% or an absolute rise of ≥.3 mg/dL. The AKI recovery was determined by comparing baseline sCr levels before drug initiation with pre‐AKI values. Results Among patients, 17.1% on SGLT2is and 25.6% on DPP4is initiated therapy within 1 month after AKI. AKI near‐full recovery (<1.1) was observed in 30.7% of SGLT2i users and 31.4% of DPP4i users before drug initiation. Compared to those with remote AKI (4–5 years prior), the risk of adverse kidney events increased only when SGLT2i therapy began within 3 months after AKI (adjusted HR: 2.15; [95% CI: 1.13–4.10]). However, for DPP4i users, the risk remained elevated for up to a year. A U‐shaped association between AKI recovery and kidney outcomes was observed in DPP4i users, with both excessive (<1.0) and impaired (≥1.1) recovery increasing risk. In contrast, impaired recovery did not worsen kidney outcomes in SGLT2i users. The treatment benefits of SGLT2i over DPP4i were consistent across varying AKI intervals and recovery examined as a continuous variable. Conclusions SGLT2i therapy demonstrated consistent benefits across different AKI intervals and recovery levels, making it a preferable option for patients at risk of AKI.

Background Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and the pulmonary vein (PV) is the most important AF trigger. Neuregulin 1β (NRG1β), which is elevated in patients with paroxysmal AF, may activate signalling pathways that mediate cellular adaptations and subsequent stress in the myocardium. The objectives of this study were to study the effects of NRG1β on the PVs and explore the underlying mechanisms. Methods A conventional microelectrode, a whole‐cell patch clamp, Western blotting and immunofluorescent confocal microscopy were used to investigate electrical activity, calcium (Ca²⁺) regulation, protein expression, ionic currents, reactive oxygen species and cytosolic sodium ([Na⁺]i) in isolated rabbit PV tissue and single cardiomyocytes with or without NRG1β (10 nM) incubation for 4 h. Results NRG1β‐treated PVs had faster beating rates and a higher incidence of triggered activity than control PVs. The increased PV spontaneous beating rate induced by NRG1β could be mitigated by ranolazine (a late Na⁺ current inhibitor, 10 μM), KN93 (1 μM) and AIP (1 μΜ) (CaMKII inhibitors) and AKTi (AKT‐1/2 inhibitor, 10 μM). NRG1β‐treated PV cardiomyocytes demonstrated larger late Na⁺ and Na⁺‐Ca²⁺ exchanger current than control PV cardiomyocytes. AIP decreased late Na⁺ current in NRG1β‐treated PV cardiomyocytes. Furthermore, NRG1β‐treated PV cardiomyocytes had smaller intracellular Ca²⁺ transients and reduced sarcoplasmic reticulum Ca²⁺ contents, but higher levels of [Na⁺]i, oxidative stress and RyR‐dependent SR Ca²⁺ leak than control PV cardiomyocytes. The increased RyR‐dependent SR Ca²⁺ leak by NRG1β could be alleviated by KN93. Additionally, NRG1β–treated PV cardiomyocytes exhibited upregulated AKT, pAKT, ERK, pERK, CaMKII and pCaMKII, while SERCA2a and PLB were downregulated. AKTi can downregulate oxi‐CaMKII and CaMKII in NRG1β–treated PV cardiomyocytes. Conclusion By modulating electrophysiological characteristics, Ca²⁺ homeostasis, and enhancing oxidative stress through AKT/CaMKII signalling, NRG1β increased PV arrhythmogenesis with increasing RyR‐dependent SR Ca²⁺ leak of PV cardiomyocytes.

This study interrogates whether mental toughness (MT) and self-compassion (SC)—historically framed as oppositional constructs—can coexist synergistically among NCAA Division II, III, and NAIA collegiate athletes, with mindfulness as a hypothesized mediator. A cross-sectional survey of 396 participants (mean age: 19.8 yrs ± 1.9 SD; females: 51%), revealed a robust MT–SC correlation (r = 0.46), which attenuated to 0.31 when mindfulness was modeled, signaling its role as a partial mediator. Hierarchical regression controlling for sex showed that MT and sex together explained 22% of the SC variance (∆R2 = 0.22, p < 0.001). Adding mindfulness increased the total explained variance to 39% (∆R2 = 0.17, p < 0.001). Females scored slightly lower on SC (β = –0.14, SE = 0.05, p = 0.008). Sobel testing confirmed significant partial mediation (Z = 7.22, p < 0.001), with mindfulness explaining 33% of MT’s total effect on SC. Mindfulness-based interventions that exploit athletes’ intrinsic attentional resources can simultaneously enhance mental toughness and self-compassion. By reconciling performance-oriented rigor with resilient self-regard, such strategies hold promise for athletes operating at diverse competitive levels.

Context Primary aldosteronism (PA) is a major cause of hypertension and cardiovascular disease; however, diagnosing PA remains challenging. Objective We investigated whether deep proteomic analyses could be used to diagnose unilateral PA in hypertensive patients. Methods We enrolled 52 patients with unilateral PA and 46 with essential hypertension (EH) and divided them into training and validation cohorts. Plasma samples were collected at baseline from all patients and again from PA patients after adrenalectomy. Deep proteomic analysis was performed to identify peptide signatures used to develop a classification model distinguishing PA from EH in the training cohort. The classification model was subsequently tested in the validation cohort and post‐adrenalectomy PA patients. Results After proteomic analysis, six peptide features including HBB, FIBA, Complement CO7, ALBU, C4BPA, and A2AP were selected to generate risk scores and develop a classification model for distinguishing unilateral PA from EH. Risk scores were significantly higher in PA patients compared to those with EH. The classification model had a sensitivity and specificity of 80.5% and 83.3%, respectively, for diagnosing unilateral PA in the training cohort, and 81.8% and 80.0% in the validation cohort. The model demonstrated strong performance with an area under the curve of .92 for distinguishing hypertensive patients with or without PA. Post‐unilateral adrenalectomy, the risk scores showed a significant decrease. Conclusions Proteomic analysis can identify peptide signatures that effectively distinguish unilateral PA from EH. These findings underscore the potential utility of proteomics as an adjunct diagnostic and monitoring tool in the clinical management of PA.

Background Acute myocardial infarction (AMI) remains one of the leading causes of mortality worldwide. Recently, a cardioprotective effect of clusterin (CLU), a ubiquitous extracellular chaperone, has been reported. However, the underlying mechanisms remain unresolved. We hypothesized that CLU exerts its protective effect on AMI by neutralizing cytotoxic and proinflammatory properties of extracellular histones, a new class of damage‐associated molecular patterns (DAMPs), that are released after massive cell injury. Methods and Results In vitro, we showed that exogenous CLU reduces histone‐induced cell death in H9C2 cells after hypoxia−reoxygenation (.78 ± .15 vs. 1.39 ± .20; p = .0059). Moreover, we found increased CLU protein levels in the ischemic zone vs. non‐ischemic zone after AMI in mice (p < .05). Correspondingly, CLU‐deficient (CLU−/−) mice presented significantly increased infarct size vs. wild‐type (CLU+/+) mice (46.29 ± 5.13% vs. 27.47 ± 1.92%; p = .0176). This cardioprotective effect of CLU is accompanied by an attenuation of the post‐AMI proinflammatory response through a decrease in the expression of proinflammatory cytokines interleukin (IL)‐6 and IL‐1β, a decrease in phosphorylated nuclear factor kappa B (NF‐kB) p65, as well as a decrease in the activation of the nucleotide‐binding oligomerization domain (NOD)‐like receptor pyrin domain containing 3 (NLRP3) inflammasome. Also, we found that in patients with acute ST‐segment elevation myocardial infarction (STEMI), circulating CLU‐histone complexes were significantly increased compared to healthy controls (p < .001). Conclusions From these results, CLU protects the heart from inflammatory injury in AMI and this cardioprotection is due at least in part to its ability to neutralise extracellular histones released from the damaged tissue.

Background In the era of precision medicine, cardiac multimodality imaging plays a vital role in diagnosing, managing, and monitoring pericarditis. This condition, often marked by inflammation and recurrent episodes, requires precise imaging techniques to guide diagnosis and therapeutic decisions. Methods We carefully reviewed the medical literature for high‐quality data regarding the use of multimodality imaging in pericarditis and the precious value of the novel concept of imaging‐guided therapy. Results While echocardiography remains the cornerstone for detecting pericardial effusion and evaluating hemodynamics, its limited ability to characterize inflammation has driven the use of advanced modalities such as cardiac magnetic resonance imaging (CMR), cardiac computed tomography (CT), and positron emission tomography (PET). CMR offers superior visualization of pericardial inflammation through late gadolinium enhancement, aiding in identifying patients who may benefit from targeted anti‐inflammatory therapies. CT imaging, with its high spatial resolution, aids in detecting pericardial calcifications and thickening, particularly in constrictive pericarditis. PET, often combined with CT, is a valuable tool for quantifying metabolic activity, allowing the detection of active inflammation, particularly in complex or refractory cases. Multiple imaging targets have been identified as essential biomarkers to confirm the inflammatory phenotype, assess treatment response, and monitor for complications. Conclusion Considering the inherent limitations of each imaging modality, the integration of imaging findings with clinical and biomarker data may aid clinicians in tailoring therapy according to different clinical scenarios and better stratification of patients who may benefit from IL‐1 blockade. This review explores the valuable role of cardiac multimodality imaging‐guided therapy in managing pericarditis.

Elevated Lp(a) is recognized as a significant independent risk factor for atherosclerotic cardiovascular diseases, including coronary artery disease, stroke and aortic valve stenosis. Notably, Lp(a) exhibits unique pro‐inflammatory and pro‐thrombotic properties contributing to its pathogenic role in cardiovascular disease. Although interventions targeting interleukin‐6 (IL‐6) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to reduce Lp(a) levels, the extent to which this reduction contributes to their overall cardiovascular benefits remains uncertain. Recent clinical trials have demonstrated that small interfering RNA (siRNA) therapies are effective in lowering Lp(a) levels, prompting ongoing investigations into their potential to improve cardiovascular outcomes. These developments highlight the clinical significance of targeting Lp(a) as a therapeutic strategy. This paper offers a comprehensive review of the pathophysiological role of Lp(a) as an independent cardiovascular risk factor, followed by an in‐depth analysis of siRNA‐based therapeutics designed to target Lp(a). It examines their mechanisms of action, clinical efficacy and safety profiles, while also addressing potential risks, limitations and challenges associated with Lp(a)‐modulating siRNA treatments. Additionally, the review discusses other RNA‐based therapeutic approaches for Lp(a) reduction, along with an overview of ongoing clinical trials. Finally, future perspectives are considered to assess the evolving therapeutic landscape and the potential advancements in Lp(a)‐targeting strategies for improving cardiovascular outcomes.

Background Platelets play a crucial role in immune responses and haemostasis. Among them, reticulated platelets (RPs) have gathered attention for their association with prothrombotic states and as a potential biomarker for cardiovascular events. However, the sex‐specific prognostic value of RPs remains underexplored. Objective This study aimed to systematically review and analyse sex‐specific differences in the prognostic role of RPs in cardiovascular disease. Methods We conducted a comprehensive search on studies that reported patient outcomes related to RPs. Study authors were contacted to provide sex‐specific patient‐level data. Two studies were excluded due to data unavailability. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Secondary endpoints included cardiovascular death, myocardial infarction, stroke, urgent revascularization, and bleeding incidents. All outcomes were stratified by sex. Results The analysis included 5 studies, reporting outcomes in 1835 patients (527 females and 1308 males). RPs are a significant predictor of MACCE independently of sex males (OR 1.99 [95% CI 1.3, 3.05; I ² = 29%]), females (2.29 [95% CI 1.31, 3.99; I ² = 10%]). For cardiovascular death RPs were predictive in females (OR 3.29 [95% CI 1.69, 6.40] I ² = .83%) and showed a trend toward significance in males (OR 2.19 95% CI [.98, 4.9] I ² = 42.72%). No sex‐specific differences were observed in all other secondary endpoints. Conclusion RPs significantly predict MACCE in cardiovascular disease independently from sex and may have a stronger association with cardiovascular death in females. Further research is needed to explore the sex‐specific mechanisms of RPs' prognostic value.

Introduction Fatty liver disease, encompassing nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction‐associated fatty liver disease (MAFLD), and the recently redefined metabolic dysfunction‐associated steatotic liver disease (MASLD), is a growing global health concern with significant cardiovascular implications. Peripheral artery disease (PAD), a common manifestation of systemic atherosclerosis, shares key pathophysiological mechanisms with fatty liver disease, including insulin resistance, systemic inflammation and endothelial dysfunction. Although emerging evidence suggests a link between fatty liver disease and PAD, the nature and extent of this association remain unclear. This systematic review synthesizes current research evaluating the relationship between fatty liver disease and PAD. Methods A systematic search of PubMed, Embase and Scopus was conducted up to December 19, 2024, following PRISMA 2020 guidelines. Eligible observational studies assessing PAD in MASLD, MAFLD or NAFLD patients were included. Quality assessment was performed independently by two reviewers using the Newcastle‐Ottawa Scale (NOS). Results Eleven observational studies, including approximately 848,027 participants, were analysed. Most studies reported a significant association between NAFLD or MAFLD and increased PAD risk, particularly in individuals with type 2 diabetes and metabolic syndrome. Studies using MAFLD criteria demonstrated a stronger association with PAD than those using NAFLD definitions. The presence of hepatic fibrosis was linked to a higher PAD risk in some studies. However, not all studies found a consistent relationship, and a few reported no independent association between fatty liver disease and PAD, highlighting the need for further research. Notably, none of the included studies used MASLD criteria. Conclusions Patients with NAFLD or MAFLD, particularly those with metabolic comorbidities, may have an elevated risk of PAD. The severity of liver disease, including fibrosis, appears to contribute to this risk. Future studies should incorporate MASLD definitions and advanced diagnostic methods to clarify this relationship and guide clinical strategies for integrated cardiovascular and liver disease management.

Background A strong correlation exists between low‐density lipoprotein cholesterol (LDL‐C), non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and apolipoprotein B100 (apoB). However, evidence suggests that LDL‐C and non‐HDL‐C may underestimate apoB, potentially obscuring residual cardiovascular risk. Furthermore, interactions between apoB and lipoprotein(a) are implicated in atherogenesis. This study sought to determine whether discordance between apoB, LDL‐C, non‐HDL‐C, or lipoprotein(a) is associated with 20‐year atherosclerotic cardiovascular disease (ASCVD) risk within a cohort of apparently healthy adults. Methods A cohort of 3042 CVD‐free adults residing in greater Athens, Greece, was recruited in 2002. A 20‐year follow‐up was conducted in 2022, comprising n = 2169 participants, of which n = 1988 had complete data for cardiovascular disease incidence. Discordance between biomarkers was defined based on recommended lipid thresholds. Cox proportional hazards models were used to assess the association between discordant/concordant biomarker pairs and 20‐year ASCVD risk. Results ApoB strongly correlated with LDL‐C and non‐HDL‐C, though concordance was limited. Increased 20‐year ASCVD cumulative incidence with elevated apoB levels, beyond LDL‐C, non‐HDL‐C, and lipoprotein(a). Discordance analysis revealed that elevated apoB independently predicted increased 20‐year ASCVD risk, regardless of non‐HDL‐C and lipoprotein(a). However, this effect was observed only on concomitantly elevated LDL‐C levels. Incorporating apoB into the assessment of traditional modifiable risk factors elucidated part of the previously residual 20‐year ASCVD risk, especially in individuals with elevated LDL‐C, non‐HDL‐C, or lipoprotein(a) levels. Conclusions ApoB may be a superior biomarker for assessing long‐term ASCVD risk, indicating that apoB‐containing lipoprotein particle number, rather than cholesterol content, is a more robust predictor of ASCVD risk.

Background Type 2 diabetes (T2D) is a comorbidity commonly associated with obesity. Elevated concentrations of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) are associated with these conditions, making both cytokines interesting candidates to combat them. This study aimed to analyse the relationship between changes in plasma GDF15 and FGF21 levels and the resolution of T2D or obesity improvements after bariatric surgery. Methods Plasma samples from 104 patients (52 with obesity and normoglycemia and 52 with obesity and impaired glucose tolerance or T2D) were analysed before and after Roux‐en‐Y‐gastric bypass surgery. Results Plasma GDF15 levels increased significantly after bariatric surgery in patients with obesity and normoglycemia ( p < 0.01), as well as in those with obesity and impaired glucose tolerance or T2D ( p < 0.05). This increase was significant in patients analysed up to 8 months after surgery in both groups ( p < 0.01) but not in those analysed between 8 to 15 months after surgery, suggesting that GDF15 concentrations exhibit an early increase after surgery but may return to baseline levels over time. In contrast, plasma FGF21 levels after bariatric surgery decreased significantly in patients with impaired glucose tolerance or T2D ( p < 0.05). Pre‐surgery FGF21 concentrations were negatively correlated with the percentage of excess weight loss and the percentage of fat loss. Conclusions GDF15 and FGF21 exhibit a different behaviour after Roux‐en‐Y‐gastric bypass surgery, with FGF21 being more closely associated with glycemic status and weight loss. Elevated pre‐surgery FGF21 concentrations could predict a higher difficulty in losing the excess weight after surgery.

Background There is divergent evidence of triglycerides on cardiovascular prevention that might be explained by confounding factors. Methods We performed a multicenter and retrospective study using the ongoing registries of acute coronary syndrome (ACS) patients of 8 hospitals from Spain. Triglycerides were measured during the hospitalization, and mortality and major adverse cardiovascular events (MACE) were analysed through follow‐up. Results We included 14,483 patients discharged after an ACS. Median triglycerides level was 120.5 (interquartile range [IQRS] 90–197) mg/dL and was slightly higher in patients with recurrent ACS (135 IQR 98–186 vs. 129 IQR 95–175; p < .01). Through the follow‐up, 34.7% of the patients experienced a first MACE rate and 15.0% died. Multivariate analysis identified that triglycerides levels were associated with a higher risk of MACE (HR 1.01 95% CI 1.00–1.02, p = .021) but not with all‐cause mortality (HR: 1.00 95% .99–1.02, p = .17). A significant interaction ( p = .01) was observed for triglycerides and previous ACS for both endpoints and, therefore, analyses were performed separately. Triglycerides were only associated with a higher risk of MACE in patients with recurrent ACS (HR 1.03 95% CI 1.01–1.05, p = .012) and a higher risk of death in patients with a first ACS (HR 1.02 95% CI 1.01–1.04, p = .02). Conclusions Previous ACS modifies the risk of triglycerides on MACE and mortality in patients discharged after an ACS. Triglycerides might be considered a target for treatment in patients after a first or recurrent ACS, although the expected benefit on outcomes might be different.

Background Mean platelet volume (MPV) has been reported significantly higher in patients with metabolic dysfunction associated steatotic liver disease (MASLD), suggesting a thrombogenic effect with an inconclusive link to excess risk for cardiovascular disease (CVD). The aim of this cross‐sectional study was to elucidate the role of MPV in MASLD and review the literature. Methods A cohort of consecutive biopsy‐proven MASLD patients was retrospectively investigated for possible associations of MPV with histological features of the disease and, separately, with patients' estimated risk for CVD. CVD Risk was assessed with three different scores: QRISK2, HellenicSCORE II and NAFLD CV Risk. Laboratory investigation included calculation of insulin resistance with the Homeostasis Model Assessment (HOMA) and measurement of serum adiponectin in a subgroup of patients. Results In a total of 139 MASLD patients, 56 (40.3%) with advanced fibrosis (F3/F4) steatohepatitis were included. MPV exceeded the upper limit of normal (=10 fl) in a significant proportion of study participants ( n = 28.1%), with an overall mean of 9.4 ± .9 fl. Statistically significant associations of MPV with platelet count (Pearson correlation, p < .001), with fibrosis stage (one‐way ANOVA, p = .040), with adiponectin (Spearman's correlation, p = .033), and all three different CVD Risk scores were found. Finally, a strong negative correlation was detected between serum adiponectin and CVD Risk scores. Conclusions In this study's cohort of MASLD patients, high MPV was associated with higher fibrosis stages and with increased estimated risk for CVD. Correlations of serum adiponectin to MPV and CVD risk scores support its implication as a cytokine‐mediator that has to be further studied.

Background Torque teno virus (TTV) is not known to cause disease in humans; however, chronic inflammatory conditions and immunosuppression states can favour TTV replication. This study aimed to verify the effectiveness of TTV as an immune biomarker. Methods The protocol of this review was registered in PROSPERO (CRD42022331049) and performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Results Thirty‐three articles were selected and different groups of patients were assessed. In the solid organ and hematopoietic stem cell transplant groups, most studies reported that TTV viral load (VL) was highly detectable after transplantation and compared to controls, but the association with immune parameters showed conflicting results. In melanoma patients, no statistical difference in TTV VL was identified between susceptible and treatment‐resistant patients. In lung cancer patients, viral load increases significantly with disease progression but decreases after chemotherapy. HIV‐positive patients showed a higher VL than controls, but an inverse correlation with CD4+ was observed in half of the studies. Although 57.14% of all studies presented a low risk of bias, significant differences were observed between studies, particularly in the choice of the analyzed outcome, the parameter used to evaluate the patient's immune status, the presence of a control group, and the sample collection time points. Conclusions Although TTV seems to have the potential to be a promising biomarker of immunosuppression, further high‐quality prospective clinical studies are still needed.