A comparison of simplified or conventional antithrombotic regimens after left atrial appendage closure in patients at high bleeding risk: the PLATEBRISK study.

BACKGROUND: Antithrombotic treatment (ATT) post-left atrial appendage occlusion (LAAO) remains controversial. Furthermore, most of the patients undergoing LAAO are at a very high bleeding risk. AIMS: This study aimed to compare a simplified versus conventional ATT after LAAO in very high bleeding risk patients. METHODS: This is a multicentre, retrospective study including very high bleeding risk patients, according to the Bleeding Academic Research Consortium (BARC) definition, who underwent LAAO. These included patients at >4% risk of BARC 3 to 5 bleeding or >1% risk of intracranial bleeding after the procedure. Two groups were established based on the discharge ATT. The simplified group included single antiplatelet treatment or no treatment, and the conventional group comprised dual antiplatelet treatment or anticoagulation (combined or not with antiplatelet therapy). RESULTS: A total of 1,135 patients were included. The mean CHA2DS2-VASc and HAS-BLED scores were 4.5±1.5 and 3.7±1.0, respectively. There were no differences in the composite endpoint (death, stroke, transient ischaemic attack, device-related thrombus or major bleeding) between the 2 groups (hazard ratio [HR] 0.81, 95% confidence interval [CI]: 0.59-1.11; p=0.188). Although the rate of major bleeding during the first year was numerically lower in the simplified group, it did not reach statistical significance (HR 0.67, 95% CI: 0.41-1.10; p=0.104). Nonetheless, patients with previous major bleeding presented a significantly lower rate of major bleeding when using the simplified treatment (HR 0.61, 95% CI: 0.36-0.99; p=0.049). CONCLUSIONS: In patients with very high bleeding risk, a simplified ATT after LAAO seems to be as effective as conventional protocols. Furthermore, patients with a history of major bleeding experienced a lower risk of major bleeding with the simplified ATT.

Determinants of adverse outcomes following patent foramen ovale closure in elderly patients.

BACKGROUND: Limited data are available on transcatheter patent foramen ovale (PFO) closure outcomes in the elderly. AIMS: Through this study, we aimed to determine the incidence and predictors of adverse events (recurrent cerebrovascular events [CVE] and atrial fibrillation [AF]) post-PFO closure in older patients with cryptogenic events. METHODS: This multicentre international study included patients over 60 years undergoing PFO closure for cryptogenic thromboembolic events. A dedicated database compiled baseline, procedural, and follow-up data. Competing risk and adjusted outcome predictor analyses were conducted. RESULTS: A total of 689 patients were included (median age 65 years, 41.2% female, mean Risk of Paradoxical Embolism [RoPE] score 4.5). The procedural success rate was 99.4%. After a median follow-up of 2 (interquartile range 1-5) years, 66 patients (9.6%) had died. CVE and stroke rates were 1.21 and 0.55 per 100 patient-years, respectively. Diabetes (hazard ratio [HR] 3.89, 95% confidence interval [CI]: 1.67-9.07; p=0.002) and atrial septal aneurysm (ASA; HR 5.25, 95% CI: 1.56-17.62; p=0.007) increased the CVE risk. New-onset AF occurred at a rate of 3.30 per 100 patient-years, with 51.3% within one month post-procedure. Older age (HR 1.05 per year, 95% CI: 1.00-1.09; p=0.023) and the absence of hypertension (HR 2.04, 95% CI: 1.19-3.57; p=0.010) were associated with an increased risk of AF. CONCLUSIONS: Older patients undergoing PFO closure had a relatively low rate of CVE and new-onset AF after a median follow-up of 2 years. The presence of diabetes, ASA, and a more advanced age determined an increased risk of adverse clinical events. These factors may be considered in the clinical decision-making process regarding PFO closure in this challenging population.

Early and late hospital readmissions after percutaneous left atrial appendage closure.

INTRODUCTION AND OBJECTIVES: Percutaneous left atrial appendage closure (LAAC) has emerged as a nonpharmacological alternative for thromboembolic event prevention in patients with nonvalvular atrial fibrillation. However, there are few data on readmissions after LACC. The aim of this study was to determine the rate of early (≤ 30 days) and late (31-365 days) readmission after LAAC, and to assess the predictors and clinical impact of rehospitalization. METHODS: This multicenter study included 1419 consecutive patients who underwent LAAC. The median follow-up was 33 [17-55] months, and follow-up was complete in all but 54 (3.8%) patients. The primary endpoint was readmissions for any cause. Logistic regression and Cox regression analysis were performed to determine the predictors of readmission and its clinical impact. RESULTS: A total of 257 (18.1%) patients were readmitted within the first year after LAAC (3.2% early, 14.9% late). The most common causes of readmission were bleeding (24.5%) and heart failure (20.6%). A previous gastrointestinal bleeding event was associated with a higher risk of early readmission (OR, 2.65; 95%CI, 1.23-5.71). The factors associated with a higher risk of late readmission were a lower body mass index (HR, 0.96-95%CI, 0.93-0.99), diabetes (HR, 1.38-95%CI, 1.02-1.86), chronic kidney disease (HR, 1.60; 95%CI, 1.21-2.13), and previous heart failure (HR, 1.69; 95%CI, 1.26-2.27). Both early (HR, 2.12-95%CI, 1.22-3.70) and late (HR, 1.75; 95%CI, 1.41-2.17) readmissions were associated with a higher risk of 2-year mortality. CONCLUSIONS: Readmissions within the first year after LAAC (primary endpoint) were common (18.1%), were mainly related to bleeding and heart failure events, and were associated with the patients' comorbidity burden. Readmission after LAAC confers a higher risk of mortality during the first 2 years after the procedure.

Differential stability of task variable representations in retrosplenial cortex.

Cortical neurons store information across different timescales, from seconds to years. Although information stability is variable across regions, it can vary within a region as well. Association areas are known to multiplex behaviorally relevant variables, but the stability of their representations is not well understood. Here, we longitudinally recorded the activity of neuronal populations in the mouse retrosplenial cortex (RSC) during the performance of a context-choice association task. We found that the activity of neurons exhibits different levels of stability across days. Using linear classifiers, we quantified the stability of three task-relevant variables. We find that RSC representations of context and trial outcome display higher stability than motor choice, both at the single cell and population levels. Together, our findings show an important characteristic of association areas, where diverse streams of information are stored with varying levels of stability, which may balance representational reliability and flexibility according to behavioral demands.

Cross-Validation of Risk Scores for Patients Undergoing Transcatheter Edge-to-Edge Repair for Mitral Regurgitation.

Background: Risk scores may identify patients with mitral regurgitation (MR) who are at risk for adverse events, but who may still benefit from transcatheter edge-to-edge repair (TEER). We sought to cross-validate the MitraScore and COAPT risk score to predict adverse events in patients undergoing TEER. Methods: MitraScore validation was carried out in the COAPT population which included 614 patients with FMR who were randomized 1:1 to guideline-directed medical therapy (GDMT) with or without TEER and were followed for 2 years. Validation of the COAPT risk score was carried out in 1007 patients from the MIVNUT registry of TEER-treated patients with both FMR and degenerative MR who were followed for a mean of 2.1 years. The predictive value was assessed using the area under the receiver operating characteristic curve (AUC) plots. The primary outcome was all-cause mortality. Results: The MitraScore had fair to good predictive accuracy for mortality in the overall COAPT trial population (AUC, 0.67); its accuracy was higher in patients treated with TEER (AUC, 0.74) than GDMT alone (AUC, 0.65). The COAPT risk score had fair predictive accuracy for death in the overall MitraScore cohort (AUC, 0.64), which was similar in patients with FMR and degenerative MR (AUC, 0.64 and 0.66, respectively). There was a consistent benefit of treatment with TEER plus GDMT compared with GDMT alone in the COAPT trial population across all MitraScore risk strata. Conclusions: The COAPT risk score and MitraScore are simple tools that are useful for the prediction of 2-year mortality in patients eligible for or undergoing treatment with TEER.

Impact of gender on in-hospital and long-term outcomes after transcatheter aortic valve implantation: an analysis of the Spanish TAVI registry.

INTRODUCTION AND OBJECTIVES: Impact of gender on long-term outcomes after transcatheter aortic valve implantation (TAVI) remains uncertain. We aimed to investigate gender-specific differences in TAVI and its impact on outcomes. METHODS: This analysis used data from the prospective Spanish TAVI registry, which included consecutive TAVI patients treated in 46 Spanish centers from 2009 to 2021. The primary endpoint was all-cause mortality at 12 months. Secondary endpoints included in-hospital and 30-day mortality and TAVI-related complications. Adjusted logistic and Cox regression analyses were performed. RESULTS: The study included 12 253 consecutive TAVI patients with a mean age of 81.2 ± 6.4 years. Women (53.9%) were older, and had a higher STS-PROM score (7.0 ± 7.0 vs 6.2 ± 6.7; P < .001) than men. Overall, the TAVI-related complication rate was similar between women and men, with specific gender-related complications. While women more frequently developed in-hospital vascular complications (13.6% vs 9.8%; P < .001) and cardiac tamponade (1.5% vs 0.6%; P = .009), men showed a higher incidence of permanent pacemaker implantation (14.5% vs 17.4%; P = .009). There was no difference in all-cause mortality either in hospital (3.6% vs 3.6%, adjusted odds ratio [OR], 1.01; 95% confidence interval [95%CI], 0.83-1.23; P = .902), at 30 days (4.2% vs 4.2%, adjusted OR, 0.90; 95%CI, 0.65-1.25; P = .564) or at 1 year (11% vs 13%, adjusted HR, 0.94; [0.80-1.11]; P = .60). CONCLUSIONS: women treated with TAVI are older and have more comorbidities than men, leading to distinct complications between genders. Nevertheless, all-cause mortality in the short-term and at 1-year was similar between men and women.

Transapical transcatheter mitral valve replacement for mitral valve disease: an Iberian experience.

INTRODUCTION AND OBJECTIVES: Transcatheter mitral valve replacement (TMVR) is an emerging treatment alternative for mitral valve (MV) disease in patients who were ineligible for surgical intervention or edge-to-edge repair. This study aimed to assess the short- and mid-term outcomes of this procedure. METHODS: We conducted a prospective registry to include the initial experience with symptomatic, consecutive patients who underwent TMVR using the transapical Tendyne system at 7 centers in the Iberian Peninsula. Baseline clinical and imaging data, periprocedural information, and follow-up assessments were collected at 1 month and 1 year. RESULTS: A total of 40 patients (mean age 78.5 years [76-82], 47,5% males) underwent TMVR. The majority had significant surgical risk, comorbidities, and advanced functional class. All patients had significant mitral regurgitation (MR), except for 2 with severe stenosis. Previous MV intervention and off-label indication for the procedure were present in 4 (10.0%) and 8 (20.0%) patients, respectively. Technical success was recorded in 100%, device success in 95.0%, and procedural success in 85.0% at 30-day. All-cause mortality was 2.5% and 17.5% at the 1-month and 1-year follow-up, respectively. MR reduction (≤ 1) and functional class improvement (NYHA I-II) were observed at 1 year in 93.9% and 87.9% of survivors, respectively. CONCLUSIONS: Treatment with TMVR produced enduring resolution of MV disease and notable functional enhancement at 1 year of follow-up. The procedure demonstrated a satisfactory early safety profile, although 1-year mortality remained relatively high in this high-risk population.

Electrokinetic properties of NaCl solution via molecular dynamics simulations with scaled-charge electrolytes.

Scaling ionic charges has become an alternative to polarizable force fields for representing indirect charge transfer effects in molecular simulations. In our work, we apply molecular dynamics simulations to investigate the properties of NaCl aqueous solutions in homogeneous and confined media. We compare classical integer- and scaled-charge force fields for the ions. In the bulk, we validate the force fields by computing equilibrium and transport properties and comparing them with experimental data. Integer-charge ions overestimate dielectric saturation and ionic association. Both force fields present an excess in ion-ion correlation, which leads to a deviation in the ionic conductivity at higher ionic strengths. Negatively charged quartz is used to simulate the confinement effect. Electrostatic interactions dominate counter-ion adsorption. Full-charge ions have stronger and more defined adsorption planes. We obtain the electroosmotic mobility of the solution by combining the shear plane location from non-equilibrium simulations with the ionic distribution from equilibrium simulations. From the Helmholtz-Smoluchowski equation, the zeta potential and the streaming potential coupling coefficient are computed. From an atomic-scale perspective, our molecular dynamics simulations corroborate the hypothesis of maximum packing of the Stern layer, which results in a stable and non-zero zeta potential at high salinity. The scaled-charge model representation of both properties is in excellent qualitative and quantitative agreement with experimental data. With our work, we demonstrate how useful and precise simple scaled-charge models for electrolytes can be to represent complex systems, such as the electrical double layer.

Impact of gender in patients with device-related thrombosis after left atrial appendage closure - A sub-analysis from the multicenter EUROC-DRT-registry.

BACKGROUND: Device-related thrombosis (DRT) is a common finding after left atrial appendage closure (LAAC) and is associated with worse outcomes. As women are underrepresented in clinical studies, further understanding of sex differences in DRT patients is warranted. METHODS AND RESULTS: This sub-analysis from the EUROC-DRT-registry compromises 176 patients with diagnosis of DRT after LAAC. Women, who accounted for 34.7% (61/176) of patients, were older (78.0 ± 6.7 vs. 74.9 ± 9.1 years, p = .06) with lower rates of comorbidities. While DRT was detected significantly later in women (173 ± 267 vs. 127 ± 192 days, p = .01), anticoagulation therapy was escalated similarly, mainly with initiation of novel oral anticoagulant (NOAC), vitamin K antagonist (VKA) or heparin. DRT resolution was achieved in 67.5% (27/40) of women and in 75.0% (54/72) of men (p = .40). In the remaining cases, an intensification/switch of anticoagulation was conducted in 50.% (9/18) of men and in 41.7% (5/12) of women. Final resolution was achieved in 72.5% (29/40) cases in women, and in 81.9% (59/72) cases in men (p = .24). Women were followed-up for a similar time as men (779 ± 520 vs. 908 ± 687 days, p = .51). Kaplan-Meier analysis revealed no difference in mortality rates in women (Hazard Ratio [HR]: 1.73, 95%-Confidence interval [95%-CI]: .68-4.37, p = .25) and no differences in stroke (HR: .83, 95%-CI: .30-2.32, p = .72) within 2 years after LAAC. CONCLUSION: Evaluation of risk factors and outcome revealed no differences between men and women, with DRT in women being diagnosed significantly later. Women should be monitored closely to assess for DRT formation/resolution. Treatment strategies appear to be equally effective.

Early Nonprocedural Bleeding After Left Atrial Appendage Occlusion.

BACKGROUND: Patients treated with left atrial appendage occlusion (LAAO) are at high bleeding risk. Intensive antithrombotic treatment is recommended after the procedure to prevent device-related thrombosis. OBJECTIVES: This study sought to evaluate the incidence, consequences, and predictors of early nonprocedural bleeding after LAAO. METHODS: This was a multicenter study including 1,649 patients undergoing LAAO in 9 centers. Early nonprocedural bleeding was defined as bleeding unrelated to the procedure occurring within 3 months after device implantation. The severity of bleeding was defined by the Valve Academic Research Consortium-2 classification. A sensitivity analysis was performed at 45 days. RESULTS: A total of 121 (7.3%) patients experienced early nonprocedural bleeding events, and 69 (57.0%) were classified as major bleeding (4.2% of patients). Independent predictors of early nonprocedural bleeding were dual antiplatelet therapy (DAPT) at discharge (adjusted HR [aHR]: 1.61; 95% CI: 1.12-2.33; P = 0.01), prior gastrointestinal bleeding (aHR: 2.15; 95% CI: 1.38-3.35; P < 0.001), and multiple locations of prior bleeding (aHR: 2.33; 95% CI: 1.34-4.05; P < 0.001). DAPT at discharge was predictive of both all and major nonprocedural bleeding at 3 months and 45 days. After a median follow-up of 2.3 years (Q1-Q3: 1.1-4.1 years), early nonprocedural bleeding was independently associated with an increased risk of all-cause death (aHR: 1.53; 95% CI: 1.15-2.06; P < 0.001). This heightened mortality risk was similar at 45 days. CONCLUSIONS: Early nonprocedural bleeding after LAAO occurred in ∼7% of patients within 3 months, with more than one-half being classified as major bleeding. Regardless of severity, early nonprocedural bleeding was associated with increased mortality. DAPT at discharge determined an increased risk of early nonprocedural bleeding after LAAO. These results emphasize the importance of bleeding risk for determining antithrombotic strategies after LAAO.

Cell Therapy in the Treatment of Female Stress Urinary Incontinence: Current Status and Future Proposals.

BACKGROUND: Stress urinary incontinence (SUI) is a common condition with a significant impact on the quality of life of female patients. The limitations of current treatment strategies have prompted the exploration of new effective and minimally invasive alternative approaches, including cell therapy. METHODS: A literature search was conducted to update the current clinical status of stem cell therapy in the management of female stress urinary incontinence. RESULTS: Over thirty clinical studies have been designed to assess the feasibility, safety and efficacy of cell therapy for female SUI. Despite differences in cell types and protocols, the overall treatment procedures were similar. Standard subjective and objective assessment tools, and follow-up periods ranged from 6 weeks to 6 years have been used. Cell injection has shown to be a safe therapy in the treatment of female SUI. However, the results from more recent randomized trials have shown less promising results than expected in restoring continence. Heterogeneous research methodologies using different cell types and doses make it difficult to draw conclusions about effectiveness. Several key points remain that need to be further explored in future clinical trials. CONCLUSION: To advance in the development of cell therapy, it is essential to know the mechanisms involved to be able to direct it properly, its efficacy and the durability of the injected cells. Rigorous and homogenized preclinical and clinical studies that demonstrate its scope and improve its application are necessary for validation in the treatment of female SUI.

Aortic Stenosis and the Evolution of Cardiac Damage after Transcatheter Aortic Valve Replacement.

Background/Objectives: Severe aortic stenosis (AS) is the most frequent valvular heart disease. Models for stratifying cardiac damage associated with aortic stenosis have been developed to predict outcomes following valve replacement. However, evidence regarding morphological and functional evolution, as well as potential changes in the degree of cardiac damage, is limited. We aim to provide information on the evolution of cardiac morphology and the function of patients undergoing transcatheter aortic valve replacement (TAVR) who have been classified using a cardiac damage staging system. Methods: In total, 496 patients were included in the analysis, and were classified into four stages based on the extent of cardiac damage as follows: Stage 0, no cardiac damage: left ventricle global longitudinal strain (LV-GLS) < -17%; right ventricular-arterial coupling (RVAc) ≥ 0.35), and absence of significant mitral regurgitation (MR). Stage 1, left-sided subclinical damage: LV-GLS ≥ -17%. Stage 2, left-sided damage: significant MR. Stage 3, right-sided damage: RVAc < 0.35. Results: The mean age was 82.1 ± 5.9 years, and 53.0% were female. In total, 24.5% of patients met the criteria for Stage 0, and Stage 1 included 42.8% of patients, Stage 2 included 16.5%, and Stage 3 comprised 16.2% of patients. Mortality was 8.4% for stage 0, 17.4% for stage 1, 25.6% for stage 2, and 28.6% for stage 3 patients (p = 0.004). Diabetes mellitus (DM) (p = 0.047) and chronic kidney disease (CKD) (p = 0.024) were the only clinical predictors of no change or worsening in the stage of cardiac damage. Regarding echocardiographic variables, concomitant tricuspid, and mitral regurgitation, ≥ 2 were both significantly associated with no change or worsening, also (p < 0.001). Conclusions: Cardiac damage that is secondary to severe aortic stenosis has morphological and functional repercussions that, even after valve replacement, persist and might worsen the prognosis.

Echocardiographic and clinical features of patients developing prosthesis-patient mismatch after transcatheter aortic valve replacement: Insights from the Recovery-TAVR registry.

BACKGROUND: The impact of prosthesis-patient mismatch (PPM) on major endpoints after transcatheter aortic valve replacement (TAVR) is controversial and the effects on progression of heart damage are poorly investigated. Therefore, our study aims to evaluate the prevalence and predictors of PPM in a "real world" cohort of patients at intermediate and low surgical risk, its impact on mortality and the clinical-echocardiographic progression of heart damage. METHODS: 963 patients who underwent TAVR procedure between 2017 and 2021, from the RECOVERY-TAVR international multicenter observational registry, were included in this analysis. Multiparametric echocardiographic data of these patients were analyzed at 1-year follow-up (FU). Clinical and echocardiographic features were stratified by presence of PPM and PPM severity, as per the most current international recommendations, using VARC-3 criteria. RESULTS: 18% of patients developed post-TAVR. PPM, and 7.7% of the whole cohort had severe PPM. At baseline, 50.3% of patients with PPM were male (vs 46.2% in the cohort without PPM, P = .33), aged 82 (IQR 79-85y) years vs 82 (IQR 78-86 P = .46), and 55.6% had Balloon-Expandable valves implanted (vs 46.8% of patients without PPM, P = .04); they had smaller left ventricular outflow tract (LVOT) diameter (20 mm, IQR 19-21 vs 20 mm, IQR 20-22, P = .02), reduced SVi (34.2 vs 38 mL/m2, P < .01) and transaortic flow rate (190.6 vs 211 mL/s, P < .01). At predischarge FU patients with PPM had more paravalvular aortic regurgitation (moderate-severe AR 15.8% vs 9.2%, P < .01). At 1-year FU, maladaptive alterations of left ventricular parameters were found in patients with PPM, with a significant increase in end-systolic diameter (33 mm vs 28 mm, P = .03) and a significant increase in left ventricle end systolic indexed volume in those with moderate and severe PPM (52 IQR 42-64 and 52, IQR 41-64 vs 44 IQR 35-59 in those without, P = .02)). No evidence of a significant impact of PPM on overall (P = .71) and CV (P = .70) mortality was observed. Patients with moderate/severe PPM had worse NYHA functional class at 1 year (NYHA III-IV 13% vs 7.8%, P = .03). Prosthesis size≤23 mm (OR 11.6, 1.68-80.1) was an independent predictor of PPM, while SVi (OR 0.87, 0.83-0.91, P < .001) and LVOT diameter (OR 0.79, 0.65-0.95, P = .01) had protective effect. CONCLUSIONS: PPM was observed in 18% of patients undergoing TAVR. Echocardiographic evaluations demonstrated a PPM-related pattern of early ventricular maladaptive alterations, possibly precursor to a reduction in cardiac function, associated with a significant deterioration in NYHA class at 1 year. These findings emphasize the importance of prevention of PPM of any grade in patients undergoing TAVR procedure, especially in populations at risk.

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.

Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing-which produces various mature mRNAs and, eventually, protein variants from a single gene-may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes.

Superiority of 3D planimetry over pressure half-time method for the assessment of mitral valve area after percutaneous edge-to-edge mitral repair.

INTRODUCTION AND OBJECTIVES: There is limited evidence to identify the most accurate method for measuring the mitral valve area (MVA) after percutaneous edge-to-edge mitral repair. Our objective was to evaluate the optimal method in this context and its correlation with the mean transmitral gradient. METHODS: A registry of patients undergoing percutaneous mitral repair was conducted, analyzing different methods of measuring MVA and their correlation with the mean gradient. RESULTS: We analyzed data from 167 patients. The mean age was 76±10.3 years, 54% were men, and 46% were women. Etiology was degenerative in 45%, functional in 39%, and mixed in 16%. Postclip MVA measurements were 1.89±0.60 cm2 using pressure half-time (PHT), 2.87±0.83 cm2 using 3D planimetry, and the mean gradient was 3±1.19mmHg. MVA using 3D planimetry showed a stronger correlation with the mean gradient (r=0.46, P<.001) than MVA obtained by PHT (r=0.19, P=.048). Interobserver agreement was also higher with 3D planimetry than with PHT (intraclass correlation coefficient of 0.90 vs 0.81 and variation coefficient of 9.6 vs 19.7%, respectively). CONCLUSIONS: Our study demonstrates that the PHT method significantly underestimates MVA after clip implantation compared with direct measurement using transesophageal 3D planimetry. The latter method also correlates better with postimplantation gradients and has less interobserver variability. These results suggest that 3D planimetry is a more appropriate method for assessing postclip mitral stenosis.

Topical Steroid Withdrawal is a Targetable Excess of Mitochondrial NAD.

Background: Topical corticosteroids (TCS) are first-line therapies for numerous skin conditions. Topical Steroid Withdrawal (TSW) is a controversial diagnosis advocated by patients with prolonged TCS exposure who report severe systemic reactions upon treatment cessation. However, to date there have been no systematic clinical or mechanistic studies to distinguish TSW from other eczematous disorders. Methods: A re-analysis of a previous survey with eczematous skin disease was performed to evaluate potential TSW distinguishing symptoms. We subsequently conducted a pilot study of 16 patients fitting the proposed diagnostic criteria. We then performed: tissue metabolomics, transcriptomics, and immunostaining on skin biopsies; serum metabolomics and cytokine assessments; shotgun metagenomics on microbiome skin swabs; genome sequencing; followed by functional, mechanistic studies using human skin cell lines and mice. Results: Clinically distinct TSW symptoms included burning, flushing, and thermodysregulation. Metabolomics and transcriptomics both implicated elevated NAD+ oxidation stemming from increased expression of mitochondrial complex I and conversion of tryptophan into kynurenine metabolites. These abnormalities were induced by glucocorticoid exposure both in vitro and in a cohort of healthy controls (N=19) exposed to TCS. Targeting complex I via either metformin or the herbal compound berberine improved outcomes in both cell culture and in an open-label case series for patients with TSW. Conclusion: Taken together, our results suggest that TSW has a distinct dermatopathology. While future studies are needed to validate these results in larger cohorts, this work provides the first mechanistic evaluation into TSW pathology, and offers insights into clinical identification, pharmacogenomic candidates, and directed therapeutic strategies.

Impact of coronary calcium morphology on intravascular lithotripsy.

BACKGROUND: Coronary calcification negatively impacts optimal stenting. Intravascular lithotripsy (IVL) is a new calcium modification technique. AIMS: We aimed to assess the impact of different calcium morphologies on IVL efficacy. METHODS: This was a prospective, multicentre study (13 tertiary referral centres). Optical coherence tomography (OCT) was performed before and after IVL, and after stenting. OCT-defined calcium morphologies were concentric (mean calcium arc >180°) and eccentric (mean calcium arc ≤180°). The primary outcomes were angiographic success (residual stenosis <20%) and the presence of fracture by OCT in concentric versus eccentric lesions. RESULTS: Ninety patients were included with a total of 95 lesions: 47 concentric and 48 eccentric. The median number of pulses was 60 (p=1.00). Following IVL, the presence of fracture was not statistically different between groups (79.0% vs 66.0% for concentric vs eccentric; p=0.165). The number of fractures/lesion (4.2±4.4 vs 2.3±2.8; p=0.018) and ≥3 fractures/lesion (57.1% vs 34.0%; p=0.029) were more common in concentric lesions. Angiographic success was numerically but not statistically higher in the concentric group (87.0% vs 76.6%; p=0.196). By OCT, no differences were noted in final minimum lumen area (5.9±2.2 mm2 vs 6.2±2.1 mm2; p=0.570), minimum stent area (5.9±2.2 mm² vs 6.25±2.4 mm2; p=0.483), minimum stent expansion (80.9±16.7% vs 78.2±19.8%), or stent expansion at the maximum calcium site (100.6±24.2% vs 95.8±27.3%) (p>0.05 for all comparisons of concentric vs eccentric, respectively). Calcified nodules were found in 29.5% of lesions; these were predominantly non-eruptive (57%). At the nodule site, dissection was more common than fracture with stent expansion of 103.6±27.2%. CONCLUSIONS: In this prospective, multicentre study, the effectiveness of IVL followed by stenting was not significantly affected by coronary calcium morphology.

Clinical impact of complex percutaneous coronary intervention in the pre-TAVR workup.

INTRODUCTION AND OBJECTIVES: In patients undergoing percutaneous coronary intervention (PCI) in the workup pre-transcatheter aortic valve replacement (TAVR), the clinical impact of coronary revascularization complexity remains unknown. This study sought to examine the impact of PCI complexity on clinical outcomes after TAVR in patients undergoing PCI in the preprocedural workup. METHODS: This was a multicenter study including consecutive patients scheduled for TAVR with concomitant significant coronary artery disease. Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, ≥ 3 stents implanted, ≥ 3 lesions treated, bifurcation with 2 stents implanted, total stent length >60mm, or chronic total occlusion. The rates of major adverse cardiac events (MACE), including cardiovascular mortality, myocardial infarction, and coronary revascularization were evaluated. RESULTS: A total of 1550 patients were included, of which 454 (29.3%) underwent complex PCI in the pre-TAVR workup. After a median follow-up period of 2 [1-3] years after TAVR, the incidence of MACE was 9.6 events per 100 patients-years. Complex PCI significantly increased the risk of cardiac death (HR, 1.44; 95%CI, 1.01-2.07), nonperiprocedural myocardial infarction (HR, 1.52; 95%CI, 1.04-2.21), and coronary revascularization (HR, 2.46; 95%CI, 1.44-4.20). In addition, PCI complexity was identified as an independent predictor of MACE after TAVR (HR, 1.31; 95%CI, 1.01-1.71; P=.042). CONCLUSIONS: In TAVR candidates with significant coronary artery disease requiring percutaneous treatment, complex revascularization was associated with a higher risk of MACE. The degree of procedural complexity should be considered a strong determinant of prognosis in the PCI-TAVR population.

BTK drives neutrophil activation for sterilizing antifungal immunity.

We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.