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Aims: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in the real world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major cardiovascular (CV) events in the real world., Methods and Results: The lipid control outcome was the percentage of patients reaching the LDL-C target of <55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all-cause death, non-fatal MI, non-fatal stroke, and ischaemia-driven revascularization) during a follow-up in relation to quartiles of LDL-C at first lipid control. We included 771 patients with ACS from the AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischaemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C < 55 mg/dL., Conclusion: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early-strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Left ventricular (LV) ring-like scar on cardiac magnetic resonance (CMR) has been linked to malignant arrhythmias in patients with non-ischemic cardiomyopathy. This study aimed to perform a comprehensive evaluation of this phenotype and to identify risk factors for life-threatening arrhythmic events (LAEs), a composite of sudden cardiac death (SCD), aborted SCD, and sustained ventricular tachycardia., Methods and Results: One-hundred-fifteen patients (median age 39 [IQR 28-52], 42% females) were identified at 6 referral centres. Inclusion criteria were ring-like LV scar (≥ 3 contiguous segments with subepicardial/midwall late gadolinium enhancement (LGE) in the same slice) and one among: pathogenic/likely pathogenic genetic variant, family history for cardiomyopathy, or arrhythmogenic cardiomyopathy diagnosis. During the study follow-up, survival-free from LAEs was 60% (3.8 events/100 patients/year); at a median follow-up of 4.6 years (IQR 1.7-8.4) it was 84%. On multivariable analysis, anterior Q waves (HR:1.030, 95% CI:1.014-1.046, p < 0.001), QRS width (HR:4.642, 95% CI:1.296-16.628, p=0.018), and LV end-diastolic volume index (LVEDVi) (HR:1.011, 95% CI:1.001-1.021, per mL/m2 increase, p=0.040) were independently associated with LAEs; with good discrimination power (Harrell's C-index=0.796). Three risk categories were identified: normal ECG, abnormal ECG and no LAEs predictive variables, abnormal ECG and ≥ 1 LAEs predictive variables, with a decreasing survival from 100% to 65% and 49%, respectively (Log-rank test = 0.015)., Conclusions: In this study, the LV ring-like scar phenotype was associated with a high rate of malignant arrhythmias in presence of anterior Q waves, QRS prolongation, and increased LVEDVi. A normal ECG identified a lower risk subgroup., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Artificial intelligence has increasingly become an integral part of our daily activities. ChatGPT, a natural language processing technology developed by OpenAI, is widely used in various industries, including healthcare. The application of ChatGPT in healthcare is still evolving, with studies exploring its potential in clinical decision-making, patient education, workflow optimization, and scientific literature. ChatGPT could be exploited in the medical field to improve patient education and information, thus increasing compliance. ChatGPT could facilitate information exchange on major cardiovascular diseases, provide clinical decision support, and improve patient communication and education. It could assist the clinician in differential diagnosis, suggest appropriate imaging modalities, and optimize treatment plans based on evidence-based guidelines. However, it is unclear whether it will be possible to use ChatGPT for the management of patients who require rapid decisions. Indeed, many drawbacks are associated with the daily use of these technologies in the medical field, such as insufficient expertise in specialized fields and a lack of comprehension of the context in which it works. The pros and cons of its use have been explored in this review, which was not written with the help of ChatGPT., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Cardiovascular diseases (CVD) and mental health disorders (MHD) are respectively the first and second most prevalent diseases in high-income countries and the two most relevant causes of disability worldwide. The close association between the two conditions has been known for a long time and research has been able to document how the co-morbidity between cardiovascular disorders and mental health disorders is a negative prognostic factor for both conditions. This strong connection and the relevance of the impact of the association have led to define a new branch of cardiology, known as behavioral cardiology. The aim of the new branch is just to study the nexus CVD-MHD in order to prevent or decrease the burden of MHD on CVD and vice versa. This review describes the epidemiological evidence of the relationship between MHD on CVD at the state of the art among clinical research., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: To study the density, spacing, and regularity of retinal cone photoreceptors using an Adaptive Optics (AO) retinal camera (Rtx1 TM , Imagine Eyes, Orsay, France) in patients with Primary Open Angle Glaucoma (POAG) and to compare the outcomes with those of healthy age-matched control subjects., Methods: The study included 43 eyes with POAG and 31 eyes of normal subjects. POAG patients were divided into three groups according to the severity of the visual field defect. The AO Rtx1 TM was used to obtain images of the parafoveal cone mosaic to calculate cone values. Analysis was performed at two and four degrees of eccentricity from the fovea along the four meridians (nasal, temporal, superior, inferior)., Results: In POAG eyes, the mean ± standard deviation (SD) cone density at 2° considering all meridians was significantly lower than in normal controls (23,058.6 ± 3532.0 cones/mm 2 , and 25,511.7 ± 3157.5 cones/mm 2 , respectively; p = 0.003). Cone spacing was 7.3 ± 0.5 µm in POAG and 7.0 ± 0.4 µm in normal controls (p = 0.005), and cone regularity was 90.5 ± 4.9% and 93.5 ± 1.9% in POAG and normal controls, respectively (p < 0.001). At 4° similar trends were observed. However, no significant differences were found among patients with different severity of POAG (p > 0.05)., Conclusions: Using AO Rtx1 TM , significant differences in retinal photoreceptors mosaic pattern were found between POAG eyes and age-matched controls, indicating a reduction in photoreceptors in POAG. No significant differences in retinal photoreceptor values were found among the three POAG groups., (© 2024. The Author(s).)

Aim: To analyze the prevalence of anxiety and depression in a large cohort of adults with autoimmune diabetes, identifying sex-driven associated factors., Materials and Methods: In this cross-sectional study, we enrolled 553 consecutive adults with Type 1 diabetes mellitus or latent autoimmune diabetes in adults who came to the Division of Endocrinology of the S.Orsola-Malpighi Polyclinic, Bologna (Italy), to receive their second dose of SARS-CoV-2 vaccine. We administered the questionnaires: Hospital Anxiety and Depression Scale, Diabetes Distress Scale, Diabetes-related Quality of Life, Diabetes Treatment Satisfaction Questionnaire. We collected clinical and biochemical data and 14 days glucose metrics in patients with sensor use > 70% in a time span of ± 4 months from the questionnaires' administration. We excluded 119 patients from our analyses with missing data (final cohort n = 434: 79% of those enrolled)., Results: Anxiety and depression prevalence was respectively 30.4% and 10.8%. According to the multivariate analysis, higher diabete-related emotional burden, lower treatment satisfaction, but not physician-related distress, were risk factors for anxiety and depression; female sex was associated with anxiety (OR 0.51, 95% 0.31-0.81; p = 0.005); in women, depression was associated with increasing age (males vs. females OR 0.96 per 1 year increase, 95% CI 0.92-1.00; p = 0.036), whilst in men with HbA1c (OR 1.08 per 1 mmol/mol increase, 95% CI 1.03-1.13; p = 0.002)., Conclusion: Nearly 1/3 of patients with autoimmune diabetes suffers from anxiety and 1/10 from depression. These conditions are associated with independent modifiable and non-modifiable characteristics. For depression, these characteristics differ between males and females., (© 2024. The Author(s).)

Background: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are multidrug resistance (MDR) transporters that function as placental gatekeepers, lowering the fetal levels of diverse xenobiotics and toxins that may be circulating in the maternal blood throughout pregnancy. Placenta accreta spectrum (PAS) and the placenta previa (PP) disorders are obstetric pathologies encompassed by an abnormal invasion of chorionic villous tissue in the uterine wall or at the endocervical os, respectively. Given the fact that MDR transporters are involved in placentation and are highly responsive to inflammation, we hypothesized that immunostaining of P-gp and BCRP would be altered in PAS and in PP specimens., Methods: A total of 32 placental histological specimens, sorted in control (N.=8; physiological pregnancies), PAS (N.=14), and PP (N.=10), were subjected to immunohistochemistry for P-gp and BCRP transporters. Semi-quantitative scoring of the resulting immunostained area and intensity was undertaken., Results: Decreased P-gp staining intensity in the syncytiotrophoblast of the PAS compared to the control group (P<0.05) and in the PP compared to the PAS group was detected (P<0.05). Fetal blood vessel P-gp immunostaining was decreased in PAS and PP groups (P<0.001)., Conclusions: We conclude that PAS and PP histological specimens exhibit decreased immunostaning of the drug transporter P-gp, and that fetuses born from these pregnancies may be exposed to greater levels of drugs and toxins present at the maternal circulation. Futures studies should attempt to investigate the mechanisms underlying P-gp down-regulation in these obstetric pathologies.

Cardiac myxoma are the most common primary tumor of the heart in adults. In approximately 2-5%, glandular differentiation occurs within these tumors. In the presence of glandular features attention must be taken to exclude and prevent a misdiagnosis of cardiac metastases of adenocarcinoma. Nevertheless, the localization in the left atrium, the solitary disposition of the cardiac mass, the histological features and the immunohistochemistry performed, argued against the possibility of a metastatic nature of the tumor. We report the case of an 80-year-old woman, with a prior medical history of breast cancer, that underwent surgery for a cardiac myxoma that histologically showed glandular features. Herein, we highlight the importance of a careful diagnosis of this entity, as it can be easily confused for a metastasis, especially in patients with a history of malignancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for atherosclerotic cardiovascular disease (ASCVD). Few data are available on the distribution of Lp(a) levels among subjects at different cardiovascular risk and in subjects with monogenic and polygenic dyslipidemias (familial hypercholesterolemia, FH and familial hypobetalipoproteinemia type 1, FHBL1). The aim of this study was to investigate the distribution of Lp(a) plasma levels in subjects with high and low LDL-C levels (FH and FHBL1) and in the general population., Methods and Results: The study cohorts included 356 hypercholesterolemic patients, 212 carrying a FH causative mutation, 144 with clinical FH (mutation negative - FHneg), 52 FHBL1 and 797 free-living subjects. Lp(a) levels were significantly higher in FH subjects (both FH and FHneg) (median 12.46 mg/dl and 14.0 mg/dl, respectively) compared with FHBL1 and free-living subjects (7.68 mg/dl and 7.18 mg/dl, respectively). More, Lp(a) levels were similar in FH subjects carrying LDLR defective and null mutations and FHneg. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels (median 10.68 mg/dl and 9.20 mg/dl, respectively) compared with low and moderate CV risk (median 5.72 mg/dl and 7.80 mg/dl, respectively) (p < 0.0008)., Conclusions: FH subjects exhibit higher Lp(a) levels than FHBL1 and general population. Lp(a) slightly contribute to hypercholesterolemia in FH patients. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels compared with low and moderate CV risk. Combined evaluation of Lp(a) levels in FH subjects with other traditional risk factors could identify very high-risk individuals who may benefit from early aggressive treatments to avoid premature CV events., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Post-mortem interval (PMI) estimation remains one of the major challenges in forensic practice, especially for late PMIs beyond 7-10 days after the death of the subject. In 2022, an innovative method to investigate the occurrence of mutations induced by the death of a subject in the DNA of post-mortem dental pulps at different PMIs was developed, applying a next-generation sequencing (NGS) analysis. The present study aims to apply the same method of analysis to a small sample of teeth belonging to the same subject and analyzed at different PMIs/accumulated degree days (ADDs), and of teeth extracted from different subjects but analyzed at the same PMI/ADD to verify the repeatability of the results obtained in relation to the time elapsed since death. A total of 10 teeth were collected from 6 patients (3 males and 3 females) with PMI varying from 8 to 35 days, and ADD from 157.4 to 753.8. We found 1754 mutations in 56 genes, with more than 700 mutations having a prevalence > 5% and more than 300 variants considered of interest for the purposes of the study. Mutations that were not present at lower PMIs but manifested in later PMIs in pulps belonging to the same subject demonstrate that they can only have been acquired by the subject after death and according to the time elapsed since death. In total, 67 somatic mutations in 29 out of the 56 genes of the used panel occurred in a fashion that allows an association with specific PMI/ADD ranges (within 8 days, between 17 and 28, and beyond 30 days after death). The results suggest that temperature and humidity could influence the rate of DNA degeneration in dental pulps, thus PMI should be estimated in ADD more than days. The preliminary validation supports the hypothesis that the innovative method could be a useful tool for estimating the post-mortem interval even beyond the first week after death, but further analyses are needed to customize a specific genetic panel for forensic investigations and verify the influence of degenerative processes of soft tissues surrounding dental elements on DNA degeneration of pulps.

Atrial fibrillation (AF) is more common in patients with malignancies than in general population. The pathophysiological processes include the pro-inflammatory condition and the exaggerated inflammatory reaction to chemotherapy, radiotherapy, and surgery interventions. Thus, it is pivotal to decrease morbidity and mortality in this group by providing appropriate care and prevention. In this subset, the risk of thromboembolic and bleeding events is high and the common risk score such as CHA2DS2-VASc and HAS-BLED employed in non-oncologic patients have limited evidence in cancer patients. A paucity of evidence in the setting in individuals having both malignancies and atrial fibrillation entangle the clinician when it comes to therapeutic management. Tailored management is recommended of anticoagulation treatment could be difficult, and there is. In this review, we try to explain the mechanism of AF in cancer patients as well as its management in this setting., (© 2024. The Author(s).)

Background: Haemodynamic variables like right atrial pressure (RAP), cardiac index (CI), stroke volume index (SVI) and mixed venous oxygen saturation ( S vO 2 ) predict survival in patients with pulmonary arterial hypertension (PAH). However, there is the need to identify further prognostic haemodynamic parameters as well as to redefine their role in PAH risk stratification compared to current risk tools and non-invasive parameters., Methods: This cohort study includes treatment-naïve patients assessed at baseline and after first-line PAH therapy with clinical, functional, exercise, laboratory and haemodynamic evaluations. Using a stepwise multivariate Cox regression analysis, independent prognostic haemodynamic parameters were identified and stratified according to cut-offs already defined in the European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk table or defined based on the highest Chi-squared of the log-rank test. Their discriminatory power was tested for all-cause death and a combined end-point of death, hospitalisation and need of treatment escalation., Results: 794 patients with PAH were enrolled. At first follow-up, RAP and pulmonary artery elastance were independently associated with death. Because of high correlations between haemodynamic parameters, different multivariable analyses were done identifying six other variables (pulmonary arterial compliance, cardiac efficiency, pulmonary vascular resistance, S vO 2 , CI and SVI). Haemodynamic parameters were of no added prognostic value compared to ESC/ERS risk tools for the all-cause death end-point but they showed additional value to non-invasive parameters for the combined end-point and, when taken alone, had a discriminatory capacity comparable to ESC/ERS risk tools., Conclusion: Haemodynamics' discriminative ability for clinical worsening is comparable to current ESC/ERS risk tools and is of added value to non-invasive parameters., Competing Interests: Conflict of interest: F. Dardi reports consulting fees from Janssen and Chiesi Farmaceutici, and lecture fees from Janssen, in the past 36 months. Conflict of interest: D. Guarino has nothing to disclose. Conflict of interest: A. Ballerini has nothing to disclose. Conflict of interest: R. Bertozzi has nothing to disclose. Conflict of interest: F. Donato has nothing to disclose. Conflict of interest: F. Cennerazzo has nothing to disclose. Conflict of interest: M. Salvi has nothing to disclose. Conflict of interest: E. Nardi has nothing to disclose. Conflict of interest: I. Magnani has nothing to disclose. Conflict of interest: A. Manes participated on the TASC advisory board for Janssen in the past 36 months. Conflict of interest: N. Galiè reports consulting and lecture fees from Janssen and Ferrer in the past 36 months. Conflict of interest: M. Palazzini reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events, and support for attending meetings and/or travel from Janssen, in the past 36 months., (Copyright ©The authors 2024.)

Chorioangiomas are benign angiomas arising from chorionic tissue and they are the most common non-trophoblastic tumors of the placenta, as they are observed in 1% of all placentas examined. Most chorioangiomas are small and asymptomatic, often undetected during a prenatal ultrasound, and their clinical significance is still unknown. Large chorioangiomas, measuring more than 4-5 cm in diameter, can usually be detected prenatally by gray-scale or color Doppler sonography, and may be associated with maternal or fetal complications, such as preeclampsia, maternal mirror syndrome, preterm delivery, nonimmune fetal hydrops, fetal growth restriction and fetal demise. We herein describe the clinical-pathological features of a monocentric series of 30 placental chorioangiomas and discuss their clinical-pathological features and possible molecular mechanisms underlying their development., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Some data suggest the existence of intestinal inflammation in patients with non-celiac wheat sensitivity (NCWS). We aimed to verify whether fecal calprotectin (FCP), a marker of intestinal inflammation, could be used to confirm this inflammatory status and to test its diagnostic performance in differentiating NCWS from irritable bowel syndrome/functional dyspepsia (IBS/FD). We conducted a multicenter study, comparing NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge, with IBS/FD subjects. In the retrospective phase, FCP values were analyzed to define the prevalence of its positivity and its role as a NCWS diagnostic biomarker. In the prospective phase we tested the effects of a strict 6-month wheat-free diet (WFD) on FCP values. 31.3% (n = 63/201) of NCWS patients had above normal FCP values (NCWS FCP +), whereas all IBS/FD patients proved negative (P = 0.0001). FCP using a cut-off value > 41 µg/g showed a 58.6% sensitivity and a 98.0% specificity (AUC 0.755, 95% C.I. 0.702-0.837) in distinguishing NCWS from IBS/FD patients. Of the 63 NCWS FCP+, 65.1% had negative FCP values after ≥ 6 months of WFD, with a significant reduction in FCP values (P < 0.0001). All NCWS FCP- subjects still preserved negative FCP values after ≥ 6 months of WFD. Our study showed that FCP can be a useful but supplementary diagnostic marker for differentiating between NCWS and IBS/FD. Strict WFD adherence reduced FCP values, normalizing them in 65.1% of NCWS FCP + subjects. These data suggest the existence of two NCWS subgroups: NCWS FCP + characterized by a probable predominantly inflammatory/immunologic pattern and NCWS FCP- featuring non-immuno-mediated etiopathogenetic mechanisms. (Registration number NCT01762579)., (© 2024. The Author(s).)

Objectives: To explore the imaging features and the molecular characterization of adenomyosis after menopause., Study Design: An observational cross-sectional study was performed in a group of postmenopausal patients undergoing a transvaginal ultrasound (TVUS) (n = 468). Among those presenting the US criteria for adenomyosis, also confirmed by magnetic resonance imaging (MRI), previous menstrual symptoms, gynecological and obstetric history were reviewed. In a subgroup undergoing hysterectomy, uterine specimens were analyzed by histology and expression of genes implicated in the epithelial-mesenchymal transition, inflammation and fibrosis, including the sphingosine-1-phosphate (S1P) pathway, was evaluated and compared to matched non-menopausal adenomyosis specimens., Main Outcome Measures: Direct and indirect US features of adenomyosis according to Morphological Uterus Sonographic Assessment at TVUS. Molecular characterization of postmenopausal versus pre-menopausal adenomyosis samples., Results: According to TVUS and MRI, adenomyosis was identified in 49 patients (10.4 %). On US, diffuse adenomyosis was the most common phenotype, whereas internal adenomyosis with diffuse pattern and asymmetric type was the most prevalent on MRI. Molecular analysis showed that adenomyosis lesions express markers of epithelial-mesenchymal transition, inflammation and fibrosis also in postmenopausal women. By comparing the results with those from pre-menopausal samples, the expression of α smooth muscle actin (αSMA), a marker of fibrosis, was significantly greater after menopause, and altered S1P catabolism and signaling were observed., Conclusions: Adenomyosis may be identified in postmenopausal women by imaging, either TVUS or MRI, and fibrosis is one of the key features on molecular analysis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiovascular (CV) diseases account for over 4 million deaths every year in Europe and over 220 000 deaths in Italy, representing the leading cause of morbidity and mortality worldwide. The European Society of Cardiology (ESC) guidelines have visionary included in the at very high CV risk group patients without previous acute ischemic events, such as those with subclinical atherosclerosis, chronic coronary syndrome or peripheral arterial disease, familial hypercholesterolemia, diabetes mellitus with target organ damage or multiple associated risk factors, and those with high calculated CV risk score, recommending to consider them and to achieve the same LDL-cholesterol targets as for secondary prevention patients. The aim of this position paper is to provide an updated overview of ESC guidelines that focuses on these patient categories to raise awareness within the clinical community regarding CV risk reduction in this specific epidemiological context.

Resonant positron annihilation on atomic electrons provides a powerful method to search for light new particles coupled to e^{+}e^{-}. Reliable estimates of production rates require a detailed characterization of electron momentum distributions. We describe a general method that harnesses the target material Compton profile to properly include electron velocity effects in resonant annihilation cross sections. We additionally find that high-Z atoms can efficiently act as particle physics accelerators, providing a density of relativistic electrons that allows one to extend by several times the experimental mass reach.