Interplay of Age and Risk Factor Control Upon Coronary Atheroma Progression.

BACKGROUND & AIM: The extent and composition of coronary plaque, and its progression differ with patients' age. The interplay of patient's age with respect to risk factor control, upon atheroma progression has not been evaluated. We tested the hypothesis that risk factor control modulates the association between age and coronary atheroma progression. METHOD: We performed a posthoc pooled analysis of data from 10 prospective, randomised trials involving serial coronary intravascular ultrasonography (IVUS) (n=5,823). The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque. RESULTS: Mean overall age was 58±9 years (28% women). In a fully adjusted multivariable analysis (following adjustment of sex, body mass index, systolic blood pressure [SBP], smoking, high-density lipoprotein and low-density lipoprotein [LDL]-cholesterol, triglyceride levels, peripheral vascular disease, diabetes mellitus, trial, region, and baseline PAV), an increase in age by one standard deviation was linked with PAV progression (ß-estimate 0.097; 95% confidence interval 0.048-0.15; p<0.001). In patients with good risk factor control (LDL-cholesterol <1.8 mmol/L and SBP <130 mmHg), increasing age remained associated with PAV progression (0.123; 0.014-0.23; p=0.027). Lower effect sizes for the association of age with PAV progression were observed for patients with partial control of LDL-cholesterol and SBP and were not significantly associated with PAV progression when both LDL-cholesterol and SBP were not controlled (0.099; 0.032-0.167; p=0.004 and 0.042; -0.056 to 0.14; p=0.40, respectively). CONCLUSIONS: Patient age is directly associated with coronary atheroma progression independently of traditional cardiovascular risk factors. In the setting of poor risk factor control, the influence of age on coronary artery disease progression is attenuated.

Real-World Patient Eligibility and Feasibility of Transcatheter Edge-to-Edge Repair or Replacement Interventions for Tricuspid Regurgitation.

Novel transcatheter therapies for tricuspid regurgitation (TR) appear promising, yet their applicability to an all-comer TR population remains unclear. We aimed to assess the feasibility of emerging transcatheter tricuspid therapies in a real-world population with greater than or equal to moderate symptomatic TR. A total of 178 patients were referred to our center between January 2019 and December 2021 for greater than or equal to moderate symptomatic TR and were classified into 4 groups: Investigative (patients eligible for enrollment in the Triluminate, Clasp TR, and TRISCEND trials), off-label clipping, surgery, and medical treatment. A total of 10.7% of the population were deemed eligible for investigative therapies, 20.2% and 19.7% of patients were offered off-label clipping and surgery, respectively, and 49.4% received medical treatment. Common reasons for investigative therapy-related ineligibility were unsuitable anatomy (large tricuspid annulus or wide leaflet coaptation gap) and the presence of significant comorbidities. Compared with the other groups, the investigative group was less likely to harbor concomitant ≥moderate mitral regurgitation, greater than or equal to moderate right ventricular dysfunction or severe pulmonary hypertension (P < .05). At 1 year, there remained a significant reduction in TR severity in the investigative group (P < .001) in comparison with the medical treatment group. However, the results were comparable to off-label clipping (P = .60) and inferior to surgery (P =.04). Exploratory analyses failed to show evidence of differences in the rates of all-cause mortality (P =.40) and heart failure hospitalizations (P = .94) between all groups. Current real-world eligibility of TR patients for emerging transcatheter therapies remains limited, underscoring the need for continued innovative efforts to offer device therapies to a broader TR cohort.

A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.

Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.

Outcomes and Predictors of Stroke After Transcatheter Aortic Valve Replacement in the Cerebral Protection Device Era.

BACKGROUND: Studies have shown inconclusive results on the effectiveness of cerebral protection devices (CPDs) with transcatheter aortic valve replacement. We aimed to analyze the national statistics on stroke and other outcomes with CPD use. METHODS AND RESULTS: The Nationwide Readmissions Database (2017-2020) was queried to obtain data on patients undergoing transcatheter aortic valve replacement. Outcomes were compared between patients with a CPD and patients without a CPD. Of 271 804 patients undergoing transcatheter aortic valve replacement, CPD was used in 7.3% of patients. In a multivariable logistic regression analysis, CPD use was not associated with lower overall stroke rates (1.6% versus 1.9% without CPD; odds ratio, 0.95 [95% CI, 0.84-1.07]; P=0.364), but it was significantly associated with lower major stroke rates (1.2% versus 1.5% without CPD; odds ratio, 0.85 [95% CI, 0.74-0.98]; P=0.02). Patients with a CPD also had a shorter length of stay, higher routine discharges to home/self-care (74.9% versus 70.6%), and lower mortality rates (0.7% versus 1.3%). The 30-day (9.6% versus 11.7%) and 180-day (24.6% versus 28.2%) readmission rates were significantly lower in the CPD cohort. Among patients who developed stroke, patients with a CPD had more frequent routine discharges. Prior valve surgery was associated with the highest risk of overall and major stroke. CONCLUSIONS: CPD use during transcatheter aortic valve replacement was not independently associated with a lower risk of overall stroke but was associated with a lower risk of major stroke in a multivariable model. Data from future randomized trials that may offset any potential confounders in our study are required to help identify patients who would benefit from the use of these devices.

Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.

B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.

Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

Role of aortic valve replacement in moderate aortic stenosis: a 10-year outcomes study.

OBJECTIVE: Patients with moderate aortic stenosis (AS) exhibit high morbidity and mortality. Limited evidence exists on the role of aortic valve replacement (AVR) in this patient population. To investigate the benefit of AVR in moderate AS on survival and left ventricular function. METHODS: In a retrospective cohort study, patients with moderate AS between 2008 and 2016 were selected from the Cleveland Clinic echocardiography database and followed until 2018. Patients were classified as receiving AVR or managed medically (clinical surveillance). All-cause and cardiovascular mortality were assessed by survival analyses. Temporal haemodynamic and structural changes were assessed with longitudinal analyses using linear mixed effects models. RESULTS: We included 1421 patients (mean age, 75.3±5.4 years and 39.9% women) followed over a median duration of 6 years. Patients in the AVR group had lower risk of all-cause (adjusted HR (aHR)=0.51, 95% CI: 0.34 to 0.77; p=0.001) and cardiovascular mortality (aHR=0.50, 95% CI: 0.31 to 0.80; p=0.004) compared with those in the clinical surveillance group irrespective of sex, receipt of other open-heart surgeries and underlying malignancy. These findings were seen only in those with preserved left ventricular ejection fraction (LVEF) ≥50%. Further, patients in the AVR group had a significant trend towards an increase in LVEF and a decrease in right ventricular systolic pressure compared with those in the clinical surveillance group. CONCLUSIONS: In patients with moderate AS, AVR was associated with favourable clinical outcomes and left ventricular remodelling.

Transcatheter Aortic Valve Replacement in Congenital Heart Disease.

Transcatheter aortic valve replacement is not widely used in patients with congenital heart disease. We describe our single-center experience of transcatheter aortic valve replacement in congenital heart disease, demonstrating short-term feasibility and safety, role in lifetime management of congenital aortic valve disease, and use as a bridge to recovery, future surgery, or transplantation.

Bicaval TricValve Implantation in Patients With Severe Symptomatic Tricuspid Regurgitation: 1-Year Follow-Up Outcomes.

BACKGROUND: Several orthotopic transcatheter strategies have been developed to treat severe tricuspid regurgitation (TR); however, many patients are deemed unsuitable. Caval valve implantation with the TricValve system addresses this unmet need. OBJECTIVES: This study sought to determine the impact of TricValve on systemic congestion and quality of life (QOL) at 1 year. METHODS: The TRICUS (Safety and Efficacy of the TricValve® Transcatheter Bicaval Valves System in the Superior and Inferior Vena Cava in Patients With Severe Tricuspid Regurgitation) and TRICUS EURO studies were prospective, nonblinded, nonrandomized, single-arm trials representing the early-in-man experience of the TricValve system in NYHA functional class III or IV severe TR patients, optimally medicated and ineligible for open heart surgery, with significant caval backflow. The primary endpoint was QOL metrics and functional status. The 1-year results of the combined cohort are described here. RESULTS: Forty-four patients were included. Mean age was 76.2 ± 7.5 years, 81.0% were women, and the TRISCORE (risk score model for isolated tricuspid valve surgery) was 5.3 ± 1.3. Clinical improvement at 1 year was achieved in 42 (95.5%) patients, measured by (at least 1 of) an increase in ≥15 points from baseline in 12-item Kansas City Cardiomyopathy Questionnaire score, improvement to NYHA functional class to I or II, or an increase ≥40 m in the 6-minute walk test. There were 3 (6.8%) deaths at 1-year follow-up (1 cardiovascular), and the heart failure rehospitalization rate was 29.5%. Stent fracture, conduction system disturbances, or clinically significant leaflet thrombosis were not detected. Abolished hepatic vein backflow was achieved and persisted in 63.8% of the patients, contributing towards a reduction in congestive symptoms, N-terminal pro-B-type natriuretic peptide levels (P = 0.032), and diuretic treatment. CONCLUSIONS: Caval valve implantation with the TricValve system associated with meaningful 1-year clinical improvements in terms of QOL along with relatively low mortality rates. (TRICUS Study - Safety and Efficacy of the TricValve® Device; NCT03723239).

Prevalence of ATTR-CA and high-risk features to guide testing in patients referred for TAVR.

PURPOSE: Transthyretin cardiac amyloidosis (ATTR-CA) is thought to be prevalent in patients with severe aortic stenosis (AS) who are referred for transcatheter aortic valve replacement (TAVR). However, prior studies were published when TAVR was only offered to elderly, inoperable, and high-risk patients. The aim of this study was to reevaluate the prevalence of ATTR-CA in a contemporary TAVR population and identify high-risk features to guide referral for technetium-99 pyrophosphate scan (99mTc-PyP scan) screening. METHODS: Patients seen in a multidisciplinary TAVR clinic for severe AS 70 years and older were referred for a 99mTc-PyP scan to evaluate for ATTR-CA. The primary outcome was the percent with a positive scan. The discriminatory ability of high-risk features was assessed to develop a more judicious screening system. RESULTS: Over the study period, 380 patients underwent screening, and 20 patients (5.3%) had a positive scan, with 17 patients having confirmed ATTR-CA, 1 patient deferring confirmatory testing (combined 4.7%), 1 having light chain amyloidosis, and 1 negative on biopsy. Compared to other patient and echocardiographic measures, elevated NT-pro BNP (> 1000 ng/L) was the best discriminator on who should be referred for 99mTc-PyP scan screening, with a sensitivity of 90% and a negative predictive value of 99%. CONCLUSION: The prevalence of ATTR-CA may be lower in a contemporary TAVR population due to its expanded indication for low-risk patients. NT-pro BNP is a simple test that can improve screening yield and more judiciously guide screening for ATTR-CA in this at-risk population. Comparison of the original versus the proposed algorithm.

Pacing-Related Differences After SAPIEN-3 TAVI: Clinical and Echocardiographic Correlates.

Data regarding the impact of pacing on outcomes after transcatheter aortic valve implantation (TAVI) is evolving especially with regards to pre-existing permanent pacemaker (PPM). We examined the impact of new and previous PPM on the clinical and hemodynamic outcomes after SAPIEN-3 TAVI. We included all consecutive patients who underwent transfemoral TAVI using SAPIEN-3 valve from 2015 to 2018 at our institution. Among 1,028 patients, 10.2% required a new PPM within 30 days, whereas 14% had a pre-existing PPM. The presence of either previous or new PPM had no impact on the 3-year mortality (log-rank p = 0.6) or 1-year major adverse cardiac and cerebrovascular events (log-rank p = 0.65). New PPM was associated with lower left ventricular (LV) ejection fraction (LVEF) at both 30 days (54.4 ± 11.3% vs 58.4 ± 10.1%, p = 0.001) and 1 year (54.2 ± 12% vs 59.1 ± 9.9%, p = 0.009) than no PPM. Similarly, previous PPM was associated with worse LVEF at 30 days (53.6 ± 12.3%, p <0.001) and 1 year (55.5 ± 12.1%, p = 0.006) than no PPM. Interestingly, new PPM was associated with lower 1-year mean gradient (11.4 ± 3.8 vs 12.6 ± 5.6 mm Hg, p = 0.04) and peak gradient (21.3 ± 6.5 vs 24.1 ± 10.4 mm Hg, p = 0.01), despite no baseline differences. Previous PPM was also associated with lower 1-year mean gradient (10.3 ± 4.4 mm Hg, p = 0.001) and peak gradient (19.4 ± 8 mm Hg, p <0.001) and higher Doppler velocity index (0.51 ± 0.12 vs 0.47 ± 0.13, p = 0.039). Moreover, 1-year LV end-systolic volume index was higher with new (23.2 ± 16.1 vs 20 ± 10.8 ml/m2, p = 0.038) and previous PPM (24.5 ± 19.7, p = 0.038) than no PPM. Previous PPM was associated with higher moderate-to-severe tricuspid regurgitation (35.3% vs 17.7%, p <0.001). There were no differences regarding the rest of the studied echocardiographic outcomes at 1 year. In conclusion, new and previous PPM did not affect 3-year mortality or 1-year major adverse cardiac and cerebrovascular events; however, they were associated with worse LVEF, higher 1-year LV end-systolic volume index, and lower mean and peak gradients on follow-up than no PPM.

Sex Differences in the Density of Lipidic Plaque Materials: Insights From the REASSURE-NIRS MultiCenter Registry.

BACKGROUND: Intravascular imaging has shown better response of coronary atheroma to statin-mediated lowering of low-density lipoprotein cholesterol in women. However, its detailed mechanism remains to be determined yet. Modifiability of coronary atheroma under lipid-lowering therapies is partly driven by lipidic plaque component. Given a smaller plaque volume in women, lipidic plaque features including their density may differ between sex. Therefore, the current study sought to characterize sex-related differences in the density of lipidic plaque. METHODS: We analyzed 1429 coronary lesions (culprit/nonculprit lesions=825/604) in 758 coronary artery disease patients (men/women=608/150) from the REASSURE-NIRS multicenter registry (Revelation of Pathophysiological Phenotypes of Vulnerable Lipid-Rich Plaque on Near-Infrared Spectroscopy). Total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index (=maximum 4-mm-lipid-core burden index/total atheroma volume at 4-mm segment) on near-infrared spectroscopy/intravascular ultrasound imaging at culprit and nonculprit lesions were compared in men and women. RESULTS: Statin and high-intensity statin were used in 72.4 (P=0.81) and 22.9% (P=0.32) of study subjects, respectively. Women exhibited a smaller adjusted total atheroma volume at 4-mm segment (culprit lesions: 50.3±0.4 versus 54.2±0.3mm3, P<0.001, nonculprit lesions: 31.5±3.0 versus 44.4±2.1mm3, P<0.001), whereas their adjusted maximum 4-mm-lipid-core burden index did not differ between sex (culprit lesions: 544.7±29.9 versus 501.7±19.1, P=0.11, nonculprit lesions: 288.8±26.7 versus 272.7±18.9, P=0.51). Furthermore, a greater adjusted lipid plaque density index was observed in women (culprit lesions: 18.2±0.9 versus 9.8±0.6, P<0.001, nonculprit lesions: 23.0±2.0 versus 7.8±1.4, P<0.001). These adjustments of total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index included age, body mass index, hypertension, dyslipidemia, diabetes, smoking, a history of myocardial infarction and chronic kidney disease, low-density lipoprotein cholesterol level, statin and ezetimibe use, vessel volume, and hospital unit. The aforementioned plaque features consistently existed in both acute coronary syndrome and stable coronary artery disease subjects. CONCLUSIONS: Women harbored greater condensed lipidic plaque features, accompanied by smaller atheroma volume. These observations indicate potentially better modifiable disease in women, which underscores the need to intensify their lipid-lowering therapies for further improving their outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov/; Unique identifier: NCT04864171.

Impact of C-reactive protein levels on lipoprotein(a)-associated aortic stenosis incidence and progression.

Aims: Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown. Methods and results: We investigated the association of Lp(a) with CAVS according to CRP levels in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study (n = 18 226, 406 incident cases) and the UK Biobank (n = 438 260, 4582 incident cases), as well as in the ASTRONOMER study (n = 220), which assessed the haemodynamic progression rate of pre-existing mild-to-moderate aortic stenosis. In EPIC-Norfolk, in comparison to individuals with low Lp(a) levels (<50 mg/dL) and low CRP levels (<2.0 mg/L), those with elevated Lp(a) (>50 mg/dL) and low CRP levels (<2.0 mg/L) and those with elevated Lp(a) (>50 mg/dL) and elevated CRP levels (>2.0 mg/L) had a higher CAVS risk [hazard ratio (HR) = 1.86 (95% confidence intervals, 1.30-2.67) and 2.08 (1.44-2.99), respectively]. A comparable predictive value of Lp(a) in patients with vs. without elevated CRP levels was also noted in the UK Biobank. In ASTRONOMER, CAVS progression was comparable in patients with elevated Lp(a) levels with or without elevated CRP levels. Conclusion: Lp(a) predicts the incidence and possibly progression of CAVS regardless of plasma CRP levels. Lowering Lp(a) levels may warrant further investigation in the prevention and treatment of CAVS, regardless of systemic inflammation.

Inward Displacement: A Novel Method of Regional Left Ventricular Functional Assessment for Left Ventriculoplasty Interventions in Heart Failure with Reduced Ejection Fraction (HFrEF).

BACKGROUND: Hybrid minimally invasive left ventricular reconstruction is used to treat patients with ischemic heart failure with reduced ejection fraction (HFrEF) and antero-apical scar. Pre- and post-procedural regional functional left ventricular assessment with current imaging techniques remains limited. We evaluated 'inward displacement' as a novel technique of assessing regional left ventricular function in an ischemic HFrEF population who underwent left ventricular reconstruction with the Revivent System. METHODS: Inward displacement adopts three standard long-axis views obtained during cardiac MRI or CT and assesses the degree of inward endocardial wall motion towards the true left ventricular center of contraction. For each of the standard 17 left ventricular segments, regional inward displacement is measured in mm and expressed as a percentage of the maximal theoretical distance each segment can contract towards the centerline. The left ventricle was divided into three regions, obtaining the arithmetic average of inward displacement or speckle tracking echocardiographic strain at the left ventricular base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). Inward displacement was measured using computed tomography or cardiac magnetic resonance imaging and compared pre- and post-procedurally in ischemic HFrEF patients who underwent left ventricular reconstruction with the Revivent System (n = 36). In a subset of patients who underwent baseline speckle tracking echocardiography, pre-procedural inward displacement was compared with left ventricular regional echocardiographic strain (n = 15). RESULTS: Inward displacement of basal and mid-cavity left ventricular segments increased by 27% (p < 0.001) and 37% (p < 0.001), respectively, following left ventricular reconstruction. A significant overall decrease in both the left ventricular end systolic volume index and end diastolic volume index of 31% (p < 0.001) and 26% (p < 0.001), respectively, was detected, along with a 20% increase in left ventricular ejection fraction (p = 0.005). A significant correlation between inward displacement and speckle tracking echocardiographic strain was noted within the basal (R = -0.77, p < 0.001) and mid-cavity left ventricular segments (R = -0.65, p = 0.004), respectively. Inward displacement resulted in relatively larger measurement values compared to speckle tracking echocardiography, with a mean difference of absolute values of -3.33 and -7.41 for the left ventricular base and mid-cavity, respectively. CONCLUSIONS: Obviating the limitations of echocardiography, inward displacement was found to highly correlate with speckle tracking echocardiographic strain to evaluate regional segmental left ventricular function. Significant improvements in basal and mid-cavity left ventricular contractility were demonstrated in ischemic HFrEF patients following left ventricular reconstruction of large antero-apical scars, consistent with the concept of reverse left ventricular remodeling at a distance. Inward displacement holds significant promise in the HFrEF population being evaluated pre- and post-left ventriculoplasty procedures.

Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas.

Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

The Current Landscape of Transcatheter Tricuspid Valve Intervention.

Tricuspid regurgitation (TR) is common, and its prevalence increases with age. It was previously estimated that there are 1.6 million patients in the United States with moderate or worse TR, and more contemporary data suggest the age-adjusted prevalence of TR is 0.55%. Increasing TR severity is associated with an adverse prognosis independent of the pulmonary artery pressure and the degree of right heart failure. In heart failure with reduced ejection fraction, survival is significantly worsened when moderate or severe TR is present. The mainstay of therapy has traditionally been surgery, but outcomes are poor. There has been increasing attention on the potential role of transcatheter interventions for TR. Numerous platforms are in developmental evolution, which broadly fall into 3 categories: valve replacement, valve repair (subdivided into annular, leaflet, and chordal platforms), and caval valve implantation. In this review, we examine all these strategies and devices, including guidance on how to appropriately select patients who can benefit from intervention.

Balloon Aortic Valvuloplasty in the Modern Era: A Review of Outcomes, Indications, and Technical Advances.

Balloon aortic valvuloplasty (BAV) improves the hemodynamics and symptoms of patients with severe aortic stenosis in the short term with low rates of complications, but has not been shown to be an effective destination therapy. Our pooled analysis of >14,300 patients from studies published between January 1, 1991, and April 31, 2022, reported intraprocedural mortality and in-hospital mortality rates as 1.94% (95% CI, 1.39%-2.59%) and 6.02% (95% CI, 4.83%-7.32%), respectively. Hence, BAV is primarily indicated as a bridge to aortic valve replacement/decision with secondary uses as bridge to noncardiac surgery and palliative therapy. Recent advancements in alternative access sites, balloon catheters, and lithotripsy for BAV have opened opportunities for expanded use and further improvements in complication rates. As the utilization of BAV has continually increased since the advent of transcatheter aortic valve replacement, reexamining the role and outcomes of BAV in the era of transcatheter aortic valve replacement has become increasingly important. This review focuses on the outcomes, indications, advances, and technical considerations for BAV.

Two-year outcomes after transcatheter aortic valve-in-valve implantation in degenerated surgical valves.

BACKGROUND: Transcatheter aortic valve-in-valve implantation (ViV-TAVI) has emerged in recent years as a safe alternative to redo surgery in high-risk patients. Although early results are encouraging, data beyond short-term outcomes are lacking. Herein, we aimed to assess the 2-year outcomes after ViV-TAVI. METHODS: Patients undergoing ViV-TAVI for degenerated surgical valves between 2013 and 2019 at the Cleveland Clinic were reviewed. The coprimary endpoints were all-cause mortality and congestive heart failure (CHF) hospitalizations. We used time-to-event analyses to assess the primary outcomes. Further, we measured the changes in transvalvular gradients and the incidence of structural valve deterioration (SVD). RESULTS: One hundred and eighty-eight patients were studied (mean age = 76 years; 65% males). At 2 years of follow-up, all-cause mortality and CHF hospitalizations occurred in 15 (8%) and 28 (14.9%) patients, respectively. On multivariable analysis, the postprocedural length of stay was a significant predictor for both all-cause mortality (hazard ratio [HR] = 1.1; 95% confidence interval [CI]: 1.01, 1.19) and CHF hospitalization (HR = 1.16; 95% CI: 1.07, 1.27). However, the internal diameter of the surgical valve was not associated with significant differences in both primary endpoints. For hemodynamic outcomes, nine patients (4.8%) developed SVD. The mean and peak transvalvular pressure gradients remained stable over the follow-up period. CONCLUSION: ViV-TAVI for degenerated surgical valves was associated with favorable 2-year clinical and hemodynamic outcomes. Further studies are needed to better understand the role of ViV-TAVI as a treatment option in the life management of aortic valve disease.

Methionine metabolism controls the B cell EBV epigenome and viral latency.

Epstein-Barr virus (EBV) subverts host epigenetic pathways to switch between viral latency programs, colonize the B cell compartment, and reactivate. Within memory B cells, the reservoir for lifelong infection, EBV genomic DNA and histone methylation marks restrict gene expression. But this epigenetic strategy also enables EBV-infected tumors, including Burkitt lymphomas, to evade immune detection. Little is known about host cell metabolic pathways that support EBV epigenome landscapes. We therefore used amino acid restriction, metabolomic, and CRISPR approaches to identify that an abundant methionine supply and interconnecting methionine and folate cycles maintain Burkitt EBV gene silencing. Methionine restriction, or methionine cycle perturbation, hypomethylated EBV genomes and de-repressed latent membrane protein and lytic gene expression. Methionine metabolism also shaped EBV latency gene regulation required for B cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogens in vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B cell life cycle and suggest therapeutic approaches.