Comparative analysis of the bioaccumulation of bisphenol A in the blood serum and follicular fluid of women living in two areas with different environmental impacts.

Introduction: Bisphenol A (BPA) is a common contaminant widely used in many industrial sectors. Because of its wide use and dispersion, it can be accumulated in living human bodies through both oral assumption and nondietary routes. BPA exhibits hormone-like properties, falling under the class of endocrine disruptors; therefore, it can alter relevant physiological functions. In particular, in women, it can affect folliculogenesis and therefore reproduction, contributing not only to infertility, but also to endometriosis and premature puberty. Methods: We conducted a multicenter study on 91 women undergoing a first in vitro fertilization (IVF) treatment in the Campania region (Southern Italy). We investigated the presence and concentration of BPA in serum and follicular fluids to assess the effects of airborne BPA contamination. The analysis was conducted on 32 women living in a low environmental impact (LEI) area, from the Sele Valley River and Cilento region, and 59 women living in a high environmental impact (HEI) area, the so-called "Land of Fires", a highly contaminated territory widely exposed to illegal waste practices. Results: A higher average BPA content in both blood serum and follicular fluid was revealed in the HEI group when compared with the LEI group. In addition, we revealed higher average BPA content in blood serum than in folliclular fluid in the HEI area, with opposite average content in the two fluids in the LEI zone. In addition, our results also showed a lack of correlation between BPA content in follicular and serum fluids both in the overall population and in the HEI and LEI groups, with peculiar trends in different subsets of women. Conclusion: From our results, we revealed a heterogeneity in the distribution of BPA content between serum and follicular fluid. Further studies are needed to unravel the bioaccumulation mechanisms of BPA in highly polluted and nonpolluted areas.

Prevalence of Diastolic and Systolic Mitral Annular Disjunction in Patients with Mitral Valve Prolapse.

BACKGROUNDS: Mitral annular disjunction (MAD) is commonly evaluated at end-systole. However, a systolic-only disjunction is merely apparent and two distinct phenotypes have been identified: True-MAD (atrial displacement of the posterior leaflet in diastole and systole) and Pseudo-MAD (apparent displacement in systole only). The prevalence of True-MAD and Pseudo-MAD in mitral valve prolapse (MVP) is not known. Aim of this study was to assess the prevalence of True-MAD and Pseudo-MAD in myxomatous MVP patients by transthoracic echocardiography (TTE) and to validate TTE compared to cardiac magnetic resonance (CMR) (reference standards). METHODS: Consecutive patients who underwent TTE for MVP were included. Mitral annular phenotype was evaluated in TTE parasternal long-axis view. Accuracy (against CMR) and intra/inter rater reliability of TTE were also assessed. RESULTS: Six-hundred-three consecutive patients were included. The prevalence of True-MAD and Pseudo-MAD was 7% (42) and 37% (221) (p<0.05), respectively. Accordingly, 221 of 263 (84%) patients classically classified as "MAD" would have been reclassified as Pseudo-MAD. Pseudo-MAD prevalence and systolic length increased with higher mitral regurgitation (MR) severity (23% for mild MR, 36% for moderate MR, 44% for severe MR (p<0.05); 6 ± 2 mm for mild MR; 8 ± 2 mm for moderate MR; 10 ± 2mm for severe MR (p<0.05), while True-MAD prevalence was consistent across MR grades. Pseudo-MAD was linked to systolic curling and Pickelhaube. TTE showed an overall accuracy of 0.89 (Cohen k 0.80), a substantial inter-rater agreement of 0.87 (k 0.76) and an almost perfect intra-rater agreement of 0.93 (k 0.85). CONCLUSION: True-MAD, unlike Pseudo-MAD, is rare in patients with MVP. Pseudo-MAD is associated with the grade of MR and other echocardiographic features of advanced myxomatous degeneration. TTE is an accurate and reliable first line method to assess mitral annulus morphology in MVP.

Association between CD20+ T lymphocytes and neuropsychological findings in multiple sclerosis.

BACKGROUND AND PURPOSE: CD20+ T lymphocytes are a subset of circulating T cells presenting the CD20+ receptor, a molecular marker of B lineage. CD20+ T lymphocytes are thought to play a pivotal role in multiple sclerosis (MS) pathology, especially at progressive stages. We aimed to investigate the correlation between CD20+ T lymphocytes and neuropsychological features (i.e., cognition, depression, anxiety, fatigue, and sleep quality) in MS patients. METHODS: We enrolled 90 MS patients. Each patient underwent cognitive assessment (Brief International Cognitive Assessment for Multiple Sclerosis) and psychometric assessment (modified Fatigue Impact Scale, Beck Anxiety Inventory, Beck Depression Inventory, Pittsburgh Sleep Quality Index). Cognitive status was defined through the cerebral functional score. RESULTS: Forty-four of 90 patients were relapsing-remitting (49%) and 46 were progressive patients (51%). Seventy patients (18.9%) showed CD20+ T lymphocytes in peripheral blood with a mean level of 0.38 ± 1.2%. Patients with CD20+ T lymphocytes were more likely to be at progressive phases (76.5% vs. 23.5%, p = 0.02) and showed a higher Expanded Disability Status Scale score (median [range] = 6.0 [1.5-7.5] vs. 3.5 [1-7.5], p = 0.001). Moreover, patients with CD20+ T lymphocytes showed worse cognitive functioning (p = 0.004), higher global fatigue symptoms (p = 0.02), higher cognitive fatigue (p = 0.01), higher psychosocial fatigue (p = 0.005), and a trend toward worse sleep quality (p = 0.06). CONCLUSIONS: The presence of CD20+ T lymphocytes in the peripheral blood of MS patients was associated with worse neuropsychological functioning and progressive disease stages. Peripheral CD20+ T lymphocytes could potentially serve as markers for both disease progression and development of fatigue in MS patients.

The posterior mitral leaflet overhang: A rare yet possible complication of percutaneous mitral valve procedures.

The two surgical options for mitral valve regurgitation are replacement and repair, with annuloplasty being the cornerstone of correction. In cases of repair failure, especially in high surgical risk patients, transcatheter mitral valve-in-ring (MViR) procedures represent emerging and challenging options. Among the several complications linked to this treatment, this paper delves into the role that native mitral leaflets may play in precipitating acute bioprosthesis dysfunction in the MViR procedure. The literature extensively covers complications related to the anterior leaflet, including risks such as outflow tract obstruction and residual mitral insufficiency due to interaction between native and prosthetic leaflets. Conversely, complications involving the posterior leaflet are less understood and often overlooked. In this gap in the literature, we present a clinical case highlighting how a redundant native posterior mitral leaflet can unexpectedly lead to acute severe mitral insufficiency by interfering with prosthetic leaflets.

Collagen-Based Vascular Closure Device Multicenter Italian Experience in Endovascular Aortic Aneurysm Repair Compared With Suture-Mediated Closure Vascular Device.

PURPOSE: The Manta Vascular Closure Device is a novel collagen-based vascular closure device that has been designed specifically for closure of large-bore percutaneous arterial accesses. The aim of this retrospective study is to evaluate the immediate and 30-day outcome of Manta at the completion of endovascular aneurysm repair (EVAR) or thoracic endovascular aortic repair (TEVAR). The hypothesis is that Manta is not inferior in obtaining hemostasis compared with the Perclose ProGlide Suture-Mediated Closure System device. MATERIALS AND METHODS: We recruited all the percutaneous accesses for (T)EVAR performed from January 2021 to April 2023 by all the Italian Divisions of Vascular Surgery using Manta at the time of data collection (May 2023). The primary outcome is to evaluate the incidence of complications at the puncture site after Manta implantation and at 1 month, and compare this with ProGlide. We applied the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) criteria for observational studies. RESULTS: Overall, 524 consecutive femoral accesses for (T)EVAR procedures were collected: 355 in the Manta cohort and 169 in the ProGlide cohort, respectively. The size of the sheath was 17.2±2.7 Fr for Manta, 15.7±2.3 Fr for ProGlide (p<0.001). No statistically significant differences between the groups regarding age, sex, body mass index, ultrasound-guided access, femoral calcifications, intraoperative, and 30-day complications. Successful arterial closure at groin puncture sites for (T)EVAR using Manta is 90.5% and 93.1% using ProGlide. Freedom for any reintervention for any complication is 95.5% for Manta and 96% for ProGlide. CONCLUSION: The 2 vascular closure devices have proved to be similar in terms of complications, without any statistically significant difference, although the median size of the sheaths for (T)EVAR was statistically significantly larger when Manta has been used, compared with ProGlide. CLINICAL IMPACT: Manta® is effective in the hemostasis of the access sites following the completion of (T)EVAR in this multicenter, retrospective, case-control study on 524 percutaneous femoral accesses. Compared to the more popular Proglide®, the average size of the introducers in the Manta® group was significantly larger than in the Proglide® group.

Being highly sensitive person negatively impacts on cognitive and psychosocial fatigue in multiple sclerosis patients: A cross-sectional, monocenter study.

BACKGROUND: Fatigue is a common symptom in Multiple Sclerosis (MS), but its determinants are not clarified yet. Sensory processing sensitivity (SPS) is a personality trait characterized by enhanced sensitivity towards endogenous and exogenous stimuli, and higher attention toward minimal stimuli, resulting in overarousal and fatigue. OBJECTIVE: to evaluate the association between SPS and fatigue in MS patients. METHODS: 192 consecutive MS patients (age of 43.3 ± 12.1 years; females 67.2 %; median EDSS of 2.5 (0 - 7)) underwent clinical (EDSS, age, gender), cognitive (BICAMS, Trial Making Test [TMT]), psychosocial (Beck Anxiety Inventory [BAI], Beck Depression Inventory [BDI], Modified Fatigue Impact Scale [MFIS]) and sensitivity evaluation (Highly Sensitive Person [HSP]Scale). Patients were classified as HSP if the score was greater than 14. A stepwise regression model was applied to explore association between SPS and MFIS total scores and sub-scores, by accounting for age, gender, education, EDSS, Cerebral FS scores, TMT-Part A and part B scores, BAI, BDI, and Pittsburgh Sleep Quality Index (PSQI). RESULTS: Total HSP was 17.2 ± 6.8 and 129 patients (67 %) were classified as highly sensitive persons (HSP). HSP patients were more female patients (p = 0.02) with a longer disease duration (p = 0.03). HSP people showed higher total MFIS score (27.6 ± 20.6 vs 13.2 ± 14.1, p < 0.001), higher physical MFIS score (p < 0.001), higher cognitive MFIS score (p < 0.001), higher psychosocial MFIS score (p < 0.001) vs non-HSP patients. Higher total MFIS was associated with SPS trait (coeff. 6.9, p = 0.006). Specifically, SPS trait was associated with higher cognitive MFIS (coeff. 5.3, p < 0.001) and higher psychosocial MFIS (coeff. 0.7, p = 0.02). CONCLUSION: SPS was associated with fatigue. Since SPS could be easily and quickly assessed in clinical settings, SPS could unveil a higher propensity of a patient toward fatigue occurrence over the disease course and could provide hints for possible preventive cognitive behavior therapy.

Clinical utility of the Lumipulse™ immunoassay for plasma neurofilament light chain in multiple sclerosis.

OBJECTIVE: Blood neurofilament light chain (NfL) is robustly associated with disease worsening in multiple sclerosis (MS), though potentially affected by concomitant factors also determining neuro-axonal loss. We investigated the association between plasma NfL (pNfL) measured with Lumipulse™ immunoassay and demographic and clinical variables in MS. METHODS: This cross-sectional study included 685 people with MS (age 49.7 ± 12.4 years; sex 65.55% females). On the same day, we collected plasma samples, along with demographics, comorbidities, and clinical variables (MS disease duration, expanded disability status scale (EDSS), Symbol Digit Modalities Test (SDMT), descriptor of disease progression, current disease modifying treatment (DMT), number of previous DMTs, evidence of disease activity in the past year (i.e. relapse or MRI new lesions), EDSS progression). pNfL was evaluated using Lumipulse™ fully automated chemiluminescent enzyme immunoassay. RESULTS: On multivariable linear regression model, higher pNfL was associated with higher EDSS (Coeff = 1.73; 95%CI 0.78, 2.68; p < 0.01), recent disease activity (Coeff = 15.70; 95%CI = 5.35, 26.06; p < 0.01), and presence of cardiovascular comorbidity (Coeff = 3.84; 95%CI 0.48, 7.20; p = 0.025). Lower pNfL was found in patients on DMT treatment (Coeff = -10.23; 95%CI -18.42, -2.04; p = 0.015), when compared with no DMT (reference). For 77.81% of our population there was correspondence between pNfL levels and two previously-validated cutoffs. CONCLUSIONS: pNfL measured using Lumipulse™ confirms known associations with MS activity, disability and treatments, and related confounding (e.g., cardiovascular comorbidity), thus granting further utilization in research and clinical practice.

Cardiovascular magnetic resonance parametric mapping in the risk stratification of patients affected by chronic myocarditis.

OBJECTIVES: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis. METHODS: This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher's exact test, or Mann-Whitney U-test. RESULTS: The population included 88 patients (age 43 [32-52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17-34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80). CONCLUSION: The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis. CLINICAL RELEVANCE STATEMENT: The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application. KEY POINTS: Risk stratification of patients affected by chronic myocarditis is an unmet clinical need. Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization. A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.

Distinctive clinical traits of lupus-related myocarditis: a multicentre retrospective study.

OBJECTIVES: Cardiovascular involvement in systemic lupus erythematosus (SLE) is frequent but little is known about possible distinctive traits of SLE-related myocarditis (myoSLE) in comparison to patients with SLE (onlySLE) or myocarditis alone (onlyMyo). METHODS: A retrospective analysis was performed comparing patients with myoSLE (n = 25) from three centres with consecutive patients with onlySLE (n = 279) and onlyMyo (n = 88). SLE patients were dichotomised by disease duration ≤1 vs >1 year into recent onlySLE/early myoSLE vs longstanding onlySLE/late myoSLE. Further stratification into disease duration of 1-5, 5-10 and >10 years was also performed. SLE disease activity index 2000 (SLEDAI-2K) was used to estimate disease activity. Myocarditis was diagnosed through biopsy or magnetic resonance. RESULTS: Women were significantly more frequent among myoSLE than among onlyMyo (72% vs 43%; p= 0.013). Compared with onlyMyo, myoSLE patients had a higher frequency of conduction abnormalities (22% vs 5%; p= 0.046) and presented with numerically higher frequencies of left ventricular function compromise (48% vs 30%), along with higher pro-brain natriuretic peptide levels. Inflammation markers were higher in myoSLE compared with onlyMyo and to patients with onlySLE with >10 years of disease duration. SLEDAI-2K was significantly higher in late myoSLE than in longstanding onlySLE. Antiphospholipid syndrome was more frequent in myoSLE than in onlySLE. Multivariate analysis showed an association among myoSLE, anti-beta-2-glycoprotein I antibodies (aB2GPI, p= 0.014) and a higher number of involved British Isles Lupus Assessment Group domains in patient history (p= 0.003). CONCLUSION: myoSLE has unique clinical traits compared with other forms of myocarditis and is associated with aB2GPI and a more severe SLE course.

Cardiac computed tomography with late contrast enhancement: A review.

Cardiac computed tomography (CCT) has assumed an increasingly significant role in the evaluation of coronary artery disease (CAD) during the past few decades, whereas cardiovascular magnetic resonance (CMR) remains the gold standard for myocardial tissue characterization. The discovery of late myocardial enhancement following intravenous contrast administration dates back to the 1970s with ex-vivo CT animal investigations; nevertheless, the clinical application of this phenomenon for cardiac tissue characterization became prevalent for CMR imaging far earlier than for CCT imaging. Recently the technical advances in CT scanners have made it possible to take advantage of late contrast enhancement (LCE) for tissue characterization in CCT exams. Moreover, the introduction of extracellular volume calculation (ECV) on cardiac CT images combined with the possibility of evaluating cardiac function in the same exam is making CCT imaging a multiparametric technique more and more similar to CMR. The aim of our review is to provide a comprehensive overview on the role of CCT with LCE in the evaluation of a wide range of cardiac conditions.

Recommendations for cardiovascular magnetic resonance and computed tomography in congenital heart disease: a consensus paper from the CMR/CCT Working Group of the Italian Society of Pediatric Cardiology and the Italian College of Cardiac Radiology endorsed by the Italian Society of Medical and Interventional Radiology (Part II).

Cardiovascular magnetic resonance (CMR) and computed tomography (CCT) are advanced imaging modalities that recently revolutionized the conventional diagnostic approach to congenital heart diseases (CHD), supporting echocardiography and often replacing cardiac catheterization. This is the second of two complementary documents, endorsed by experts from the Working Group of the Italian Society of Pediatric Cardiology and the Italian College of Cardiac Radiology of the Italian Society of Medical and Interventional Radiology, aimed at giving updated indications on the appropriate use of CMR and CCT in different clinical CHD settings, in both pediatrics and adults. In this article, support is also given to radiologists, pediatricians, cardiologists, and cardiac surgeons for indications and appropriateness criteria for CMR and CCT in the most referred CHD, following the proposed new criteria presented and discussed in the first document. This second document also examines the impact of devices and prostheses for CMR and CCT in CHD and additionally presents some indications for CMR and CCT exams when sedation or narcosis is needed.

Role of cardiac magnetic resonance in stratifying arrhythmogenic risk in mitral valve prolapse patients: a systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of studies investigating the diagnostic value of cardiac magnetic resonance (CMR) features for arrhythmic risk stratification in mitral valve prolapse (MVP) patients. MATERIALS AND METHODS: EMBASE, PubMed/MEDLINE, and CENTRAL were searched for studies reporting MVP patients who underwent CMR with assessment of: left ventricular (LV) size and function, mitral regurgitation (MR), prolapse distance, mitral annular disjunction (MAD), curling, late gadolinium enhancement (LGE), and T1 mapping, and reported the association with arrhythmia. The primary endpoint was complex ventricular arrhythmias (co-VAs) as defined by any non-sustained ventricular tachycardia, sustained ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac death. Meta-analysis was performed when at least three studies investigated a CMR feature. PROSPERO registration number: CRD42023374185. RESULTS: The meta-analysis included 11 studies with 1278 patients. MR severity, leaflet length/thickness, curling, MAD distance, and mapping techniques were not meta-analyzed as reported in < 3 studies. LV end-diastolic volume index, LV ejection fraction, and prolapse distance showed small non-significant effect sizes. LGE showed a strong and significant association with co-VA with a LogORs of 2.12 (95% confidence interval (CI): [1.00, 3.23]), for MAD the log odds-ratio was 0.95 (95% CI: [0.30, 1.60]). The predictive accuracy of LGE was substantial, with a hierarchical summary ROC AUC of 0.83 (95% CI: [0.69, 0.91]) and sensitivity and specificity rates of 0.70 (95% CI: [0.41, 0.89]) and 0.80 (95% CI: [0.67, 0.89]), respectively. CONCLUSIONS: Our study highlights the role of LGE as the key CMR feature for arrhythmia risk stratification in MVP patients. MAD might complement arrhythmic risk stratification. CLINICAL RELEVANCE STATEMENT: LGE is a key factor for arrhythmogenic risk in MVP patients, with additional contribution from MAD. Combining MRI findings with clinical characteristics is critical for evaluating and accurately stratifying arrhythmogenic risk in MVP patients. KEY POINTS: MVP affects 2-3% of the population, with some facing increased risk for arrhythmia. LGE can assess arrhythmia risk, and MAD may further stratify patients. CMR is critical for MVP arrhythmia risk stratification, making it essential in a comprehensive evaluation.

Establishment of a Transplantation Model of PDAC-Derived Liver Metastases.

BACKGROUND: The highly metastatic nature of pancreatic ductal adenocarcinoma (PDAC) and the difficulty to achieve favorable patient outcomes emphasize the need for novel therapeutic solutions. For preclinical evaluations, genetically engineered mouse models are often used to mimic human PDAC but frequently fail to replicate synchronous development and metastatic spread. This study aimed to develop a transplantation model to achieve synchronous and homogenous PDAC growth with controlled metastatic patterns in the liver. METHODS: To generate an orthotopic PDAC model, the DT6606 cell line was injected into the pancreas head of C57BL/6 mice, and their survival was monitored over time. To generate a heterotopic transplantation model, growing doses of three PDAC cell lines (DT6606, DT6606lm, and K8484) were injected into the portal vein of mice. Magnetic resonance imaging (MRI) was used to monitor metastatic progression, and histologic analysis was performed. RESULTS: Orthotopically injected mice succumbed to the tumor within an 11-week period (average survival time, 78.2 ± 4.45 days). Post-mortem examinations failed to identify liver metastasis. In the intraportal model, 2 × 105 DT6606 cells resulted in an absence of liver metastases by day 21, whereas 5 × 104 DT6606lm cells and 7 × 104 K8484 cells resulted in steady metastatic growth. Higher doses caused significant metastatic liver involvement. The use of K8484 cells ensured the growth of tumors closely resembling the histopathologic characteristics of human PDAC. CONCLUSIONS: This report details the authors' efforts to establish an "optimal" murine model for inducing metastatic PDAC, which is critical for advancing our understanding of the disease and developing more effective treatments.

Prognostic role of cardiovascular magnetic resonance in Takotsubo syndrome: A systematic review.

BACKGROUND: Takotsubo syndrome (TS) is characterized by transient myocardial dysfunction with outcomes ranging from favorable to life-threatening. Cardiovascular magnetic resonance (CMR) has emerged as an essential tool in its diagnosis and management and is consistently recommended by current guidelines in the diagnostic work-up. However, the prognostic value of CMR in patients with TS remains undetermined. The aim of this study was to assess the prognostic value of CMR in managing patients with TS. METHOD: PubMed, MEDLINE via Ovid, Scopus, and the Cochrane Library were searched to identify studies reporting the prognostic role of multiparameteric CMR in patients with TS with a follow-up ≥ 12 months. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), defined as all-cause mortality, cardiac death, heart failure, sudden cardiac death, recurrence of TS, and cerebrovascular events. RESULTS: Five studies with 564 patients were included for reporting correlation of CMR parameters with MACCE. Primary endpoint occurred in 69 (12%) patients. Among the CMR parameters assessed, myocardial strain parameters (including measurements of the left atrium, left and right ventricle), right ventricle involvement, and a CMR-based radiomics model demonstrated correlations with MACCE. Additionally, one study showed the predictive ability of a CMR score. CONCLUSION: The current systematic review suggests that CMR may offer prognostic insights in TS patients, underscoring its potential clinical utility for integration into clinical practice. However, scarce data are currently available; hence, further research is needed.

Rheumatic and Degenerative Mitral Stenosis: From an Iconic Clinical Case to the Literature Review.

Mitral stenosis (MS) poses significant challenges in diagnosis and management due to its varied etiologies, such as rheumatic mitral stenosis (RMS) and degenerative mitral stenosis (DMS). While rheumatic fever-induced RMS has declined in prevalence, DMS is rising with aging populations and comorbidities. Starting from a complex clinical case of DMS, the aim of this paper is to review the literature on mitral stenosis by analyzing the available tools and the differences in terms of diagnosis and treatment for rheumatic and degenerative stenosis. Emerging transcatheter techniques, such as transcatheter mitral valve replacement (TMVR) and lithotripsy-facilitated percutaneous mitral commissurotomy (PMC), represent promising alternatives for DMS patients deemed unfit for surgery. In particular, intravascular lithotripsy (IVL) has shown potential in facilitating percutaneous interventions by fracturing calcific deposits and enabling subsequent interventions. However, larger prospective studies are warranted to validate these findings and establish IVL's role in DMS management. To further enhance this technique, research could focus on investigating the long-term outcomes and durability of mitral lithotripsy, as well as exploring its potential in combination with PMC or TMVR.

Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.

Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.