Luca Liberale

Background and Aims: Takotsubo syndrome (TTS) closely mimics acute coronary syndrome (ACS). Early differentiation remains challenging because diagnosis currently relies on medical, psychiatric, and neurological history, repeated cardiac imaging, and exclusion of a culprit epicardial coronary artery lesion, generally with invasive coronary angiography (ICA). The aim of this study was to develop and externally validate a biomarker-based diagnostic score supporting the early differentiation of TTS from ACS before ICA. Methods: In this study, 3615 patients with ACS or TTS from overlapping registries were investigated. Circulating levels of established and emerging cardiovascular biomarkers were measured before ICA. A biomarker-based diagnostic score for TTS (BioTAK) was developed in a cohort of 1823 patients (ACS n = 1754; TTS n = 69) using machine learning-guided feature selection and logistic regression and externally validated in an independent cohort of 1792 patients (ACS n = 1715; TTS n = 77). Results: The final five-item score incorporated biomarkers reflecting myocardial stress (N-terminal pro-B-type natriuretic peptide), vasoconstriction and anxiety regulation (peptidylglycine α-amidating monooxygenase), atherosclerotic plaque instability (soluble lectin-like oxidized low-density lipoprotein receptor-1), and lipid metabolism (low-density lipoprotein cholesterol), along with sex. BioTAK demonstrated excellent discrimination between TTS and ACS in the development cohort [area under the receiver operating characteristic curve (AUC) .97, 95% confidence interval (CI) .95–.98] and maintained high performance on external validation (AUC .93, 95% CI .90–.96), with good calibration. Using predefined rule-in and rule-out thresholds, the score stratified almost 90% of patients to a likely diagnosis prior to ICA. Conclusions: TTS is characterized by a distinct biomarker profile reflecting pathophysiological differences from ACS. The non-subjective biomarker-based BioTAK score can support the early identification of TTS, help streamline diagnostic pathways, and might reduce potentially avoidable invasive procedures in patients presenting with suspected ACS. Clinical Trial Registration: NCT01000701, NCT01947621

Junctional cadherin 5-associated protein (JCAD/KIAA1462) is an endothelial junctional protein encoded by a locus robustly associated with coronary artery disease and myocardial infarction in genome-wide association studies. Initially identified as a structural component of endothelial cell–cell junctions, JCAD has since emerged as a mechanosensor and regulator of key intracellular pathways (i.e. Hippo/YAP, PI3K/Akt, and mitogen-activated protein kinase/extracellular signal-regulated kinase) with functional consequences for endothelial homeostasis, inflammation, and vascular tone. In this review, we summarize the current understanding of JCAD biology, from its molecular features and pathway interactions to its experimental roles in atherosclerosis, arterial thrombosis, and ischaemic stroke. We further discuss emerging translational evidence suggesting circulating JCAD as an independent predictor of adverse cardiovascular events in patients with acute coronary syndromes, and its prognostic potential in ischaemic stroke. The review also addresses the expanding biology of JCAD within the cardiovascular system, hypothesizing links to conditions, such as hypertension, heart failure with preserved ejection fraction, and calcific aortic valve disease, as well as key limitations and therapeutic challenges. Overall, the available evidence highlights JCAD as a biologically plausible and potentially clinically relevant endothelial mediator, though independent validation and substantial mechanistic work remain necessary before its translational potential can be fully realized.

ESCI Award for the Best Basic/Translational Research Article 2025. The ESCI Award for the Best Basic/Translational Research Article 2025 goes to ‘Cellular composition and transcriptomics of subcutane...

The field of reverse cardio-oncology examines how subclinical and overt cardiometabolic dysfunction—such as obesity—fuels breast cancer (BCa) risk and altered tumour biology through shared mechanisms such as chronic inflammation, hormonal dysregulation, and cellular senescence. Limitations of body mass index (BMI) have prompted the development of refined obesity phenotypes, including metabolically healthy vs unhealthy obesity and sarcopenic obesity that more accurately stratify BCa risk. Reverse cardio-oncology is conceptually distinguished from traditional cardio-oncology by focusing on how cardiometabolic impairment—even in the absence of manifest cardiovascular disease—increases BCa incidence and worsens prognosis. Within a common-soil framework, senescent adipose tissue is recognized as a key driver of breast tumour microenvironment remodelling through senescence-associated secretory phenotype (SASP), epigenetic reprogramming, and immunosenescence. Emerging translational strategies—including lifestyle modification, cardiometabolic therapies such as GLP-1 receptor agonists and SGLT2 inhibitors, and senolytic approaches—highlight opportunities to integrate cardiovascular and oncologic prevention and treatment in women with or at risk for BCa. Overall, this review synthesizes current knowledge on obesity’s mechanistic links to BCa within a reverse cardio-oncology paradigm and provides a conceptual foundation for improved risk stratification and interdisciplinary clinical management.

Background: Worsening heart failure (WHF) is a red flag in the natural history of heart failure (HF) that negatively impacts the prognosis. Urgent improvements in the management of WHF, especially among HF with reduced ejection fraction (HFrEF) patients, are needed to reduce morbidity and mortality. Results: Vericiguat is an oral soluble guanylate cyclase (sGC) stimulator that was able to reduce the composite of HF hospitalization or cardiovascular (CV) death in the VICTORIA trial and is now recommended with a IIb indication by HF guidelines of different societies. Accordingly, several observational studies confirmed the positive findings observed in the trial. Since the population with HFrEF includes a large number of older patients with multiple comorbidities and different degrees of frailty, implementation and up‐titration of guideline‐directed medical treatments (GDMTs) could be challenging due to a higher odd of side effects. To this end, vericiguat possesses many advantages: once daily administration, good tolerance, limited side effects (e.g. hypotension), no need for routine laboratory testing or therapeutic drug monitoring. This makes vericiguat a good candidate for older, frail patients in order to increase patient compliance and limit drug discontinuation caused by side effects. Conclusion: Although commonly named as the fifth pillar of GDMTs, vericiguat should be considered as soon as possible among those patients with HFrEF and a WHF episode. However, the recently published VICTOR trial has investigated the effect of vericiguat in HFrEF patients who did not experience a recent WHF and did not demonstrate a reduction in the composite outcome of HF hospitalization or CV death, while providing beneficial effects on CV and all‐cause mortality.

Background: Residual cardiovascular (CV) risk persists despite therapeutic advances. Obesity is heterogeneous, and visceral adipose tissue (VAT) dysfunction (‘adiposopathy’) complicates risk stratification. Osteopontin (OPN) is a pleiotropic mediator implicated in VAT inflammation, senescence‐associated pathways, atherosclerosis and myocardial remodelling. Methods: We performed a narrative synthesis of preclinical and clinical evidence on OPN across three domains: (i) VAT biology and senescence‐associated secretory phenotype (SASP); (ii) atherosclerosis and plaque vulnerability; and (iii) myocardial fibrosis/remodelling and cardiometabolic heart failure. We also summarize biomarker and therapeutic implications. Results: OPN is increased in obesity, particularly within VAT, where it contributes to SASP‐related signalling, macrophage dysfunction, low‐grade systemic inflammation, insulin resistance and cardiometabolic risk. Clinical and translational studies link circulating and tissue OPN levels to vascular inflammation, plaque vulnerability and adverse CV events. In the myocardium, OPN appears to act as a remodelling‐specific mediator connecting extracardiac adiposity‐related signals to interstitial fibrosis, with the strongest evidence in heart failure with preserved ejection fraction and diabetic cardiomyopathy. Across settings, OPN shows promise as an early biomarker for detection and risk stratification. Experimental modulation of OPN attenuates fibrosis and improves cardiac function in multiple models, supporting its candidacy as a mechanistic therapeutic target. Conclusions: OPN likely bridges the fat–heart axis through senescence‐related pathways and may help explain residual CV risk in obesity‐related cardiometabolic disease. Standardized assays, prospective validation and interventional studies are required to establish clinical utility for OPN as a biomarker and therapeutic target.

Background: A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low‐density lipoprotein cholesterol (LDL‐C) targets, a phenomenon referred to as residual CV risk. Methods: Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL‐C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride‐rich lipoproteins (TRL), high triglycerides (TG), low high‐density lipoprotein cholesterol (HDL‐C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non‐HDL‐C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach. Results: Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first‐line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL‐C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C‐III (ApoC3) and angiopoietin‐like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk. Conclusion: The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL‐C reduction.