2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.

BACKGROUND: The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year's worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain.

Multiple myeloma (MM) is a rarely curable malignancy of plasma cells. MM expresses B cell maturation antigen (BCMA). We developed a fully human anti-BCMA chimeric antigen receptor (CAR) with a heavy-chain-only antigen-recognition domain, a 4-1BB domain, and a CD3ζ domain. The CAR was designated FHVH33-CD8BBZ. We conducted the first-in-humans clinical trial of T cells expressing FHVH33-CD8BBZ (FHVH-T). Twenty-five patients with relapsed MM were treated. The stringent complete response rate (sCR) was 52%. Median progression-free survival (PFS) was 78 weeks. Of 24 evaluable patients, 6 (25%) had a maximum cytokine-release syndrome (CRS) grade of 3; no patients had CRS of greater than grade 3. Most anti-MM activity occurred within 2-4 weeks of FHVH-T infusion as shown by decreases in the rapidly changing MM markers serum free light chains, urine light chains, and bone marrow plasma cells. Blood CAR+ cell levels peaked during the time that MM elimination was occurring, between 7 and 15 days after FHVH-T infusion. C-C chemokine receptor type 7 (CCR7) expression on infusion CD4+ FHVH-T correlated with peak blood FHVH-T levels. Single-cell RNA sequencing revealed a shift toward more differentiated FHVH-T after infusion. Anti-CAR antibody responses were detected in 4 of 12 patients assessed. FHVH-T has powerful, rapid, and durable anti-MM activity.

Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year's worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

US Population Eligibility and Estimated Impact of Tirzepatide Treatment on Obesity Prevalence and Cardiovascular Disease Events.

PURPOSE: Tirzepatide promotes weight loss and reduces risk factors for cardiovascular disease (CVD) in adults with overweight and obesity. We examined the number of US adults eligible for tirzepatide and its impact on obesity and CVD events. METHODS: We identified US adults aged ≥ 18 years from the cross-sectional US National Health and Nutrition Examination Survey (NHANES) 2015-2018 eligible for tirzepatide based on SURMOUNT-1 trial eligibility criteria. Weight changes in SURMOUNT-1 from tirzepatide 15 mg treatment were used to project the impact on weight change and obesity prevalence in the population assuming titration to this dosage. We estimated 10-year CVD risks from BMI-based Framingham CVD risk scores before and after applying tirzepatide 15 mg treatment BMI and risk factor effects from SURMOUNT-1, the differences in estimated risks multiplied by the eligible NHANES weighted population representing the estimated "preventable" CVD events. RESULTS: We identified 4015 US adults (estimated population size of 93.4 million [M]) to fit SURMOUNT-1 eligibility criteria, representing 38% of US adults. When the effects of 15 mg tirzepatide were applied, we estimated 70.6% (65.9 M) and 56.7% (53.0 M) of adults to show ≥ 15% and ≥ 20% reductions in weight, respectively, translating to 58.8% (55.0 M) fewer persons with obesity. Among those without CVD, estimated 10-year CVD risks were 10.1% "before" and 7.7% "after" tirzepatide "treatment" reflecting a 2.4% absolute (and 23.6% relative) risk reduction translating to 2.0 million preventable CVD events over 10 years. CONCLUSION: Tirzepatide treatment in appropriate US adults may substantially reduce obesity prevalence and CVD events, impacting beneficially on associated healthcare costs.

TNF plays a crucial role in inflammation by signaling via T cell TNFR2.

TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4+ T cells to TNF and TGF-ß generated Th17 cells that express low levels of IL-17 (ROR-γt+IL-17lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system-infiltrating CD4+ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid-infiltrating CD4+ T cells from patients with multiple sclerosis. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1ß, a Th17-skewing cytokine, induced TNF and proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1ß can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.

TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis.

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2-/- mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2-/- and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

Validity of Self-testing at Home With Rapid Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Detection by Lateral Flow Immunoassay.

BACKGROUND: We explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassay (LFIA) performance under field conditions compared to laboratory-based electrochemiluminescence immunoassay (ECLIA) and live virus neutralization. METHODS: In July 2021, 3758 participants performed, at home, a self-administered Fortress LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample for assessment of immunoglobulin G (IgG) antibodies using the Roche Elecsys® Anti-SARS-CoV-2 ECLIA. We compared the self-reported LFIA result to the quantitative ECLIA and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralization. RESULTS: Almost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on ECLIA (using the manufacturer reference standard threshold for positivity of 0.8 U mL-1). Live virus neutralization was detected in 169 of 250 randomly selected samples (67.6%); 133/169 were positive with self-reported LFIA (sensitivity 78.7%; 95% confidence interval [CI]: 71.8, 84.6), 142/155 (91.6%; 95% CI: 86.1, 95.5) with ALFA, and 169 (100%; 95% CI: 97.8, 100.0) with ECLIA. There were 81 samples with no detectable virus neutralization; 47/81 were negative with self-reported LFIA (specificity 58.0%; 95% CI: 46.5, 68.9), 34/75 (45.3%; 95% CI: 33.8, 57.3) with ALFA, and 0/81 (0%; 95% CI: 0, 4.5) with ECLIA. CONCLUSIONS: Self-administered LFIA is less sensitive than a quantitative antibody test, but the positivity in LFIA correlates better than the quantitative ECLIA with virus neutralization.

Contemporary use of cardiovascular risk reduction strategies in type 2 diabetes. Insights from the diabetes collaborative registry.

BACKGROUND: Cardiovascular disease remains the primary source of morbidity and mortality in type 2 diabetes (T2D). We characterized the change over time in the use of evidence-based therapies to reduce cardiovascular risk in US patients with T2D. METHODS: Data from a longitudinal outpatient diabetes registry were used to calculate the prescription of SGLT2i or GLP-1RA over time and among those with high-risk comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], chronic kidney disease [CKD]) and a diabetes cardiovascular composite score (DCCS; calculated as: #eligible medications prescribed/#eligible medications x 100 for SGLT2i, GLP-1RA, statin, antiplatelet/anticoagulant therapy, ACEi/ARB/ARNI). Scores ranged from 0% to 100% (higher=more optimal care). RESULTS: Among 1,001,542 outpatients from 391 US sites, 51.7% patients had ASVCD, 17.7% HF, and 23.0% CKD. The percentage of patients prescribed an SGLT2i or GLP-1RA increased over time (7.3% in 2013 to 28.8% in 2019), and 18.3% of patients with ASCVD, HF, or CKD were on at least one of these medications at last follow-up vs 25.5% of patients without any of these comorbidities. Mean DCCS was 54±36%; 54±25% in patients with ASCVD, HF, or CKD vs 52±50% in patients without any of these comorbidities (P<0.001 for both). In a hierarchical linear model, male sex, and a diagnosis of CKD were independently associated with higher DCCS whereas a diagnosis of HF or ASCVD was associated with a lower DCCS. CONCLUSIONS: In a large, contemporary cohort of patients with T2D, we found improvement in the use of SGLT2i and GLP-1RA but unexpectedly lower use in patients with ASCVD, heart failure, and CKD, highlighting a treatment-risk paradox. Further education is needed to shift the understanding of these medications as tools for glucose-lowering to cardiovascular risk reduction and to improve their implementation in clinical practice.

Efficient recall of SARS-CoV-2 variant-reactive B cells and T responses in the elderly upon heterologous mRNA vaccines as boosters.

Waning antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of variants of concern highlight the need for booster vaccinations. This is particularly important for the elderly population, who are at a higher risk of developing severe coronavirus disease 2019 (COVID-19) disease. While studies have shown increased antibody responses following booster vaccination, understanding the changes in T and B cell compartments induced by a third vaccine dose remains limited. We analyzed the humoral and cellular responses in subjects who received either a homologous messenger RNA(mRNA) booster vaccine (BNT162b2 + BNT162b2 + BNT162b2; ''BBB") or a heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ''BBM") at Day 0 (prebooster), Day 7, and Day 28 (postbooster). Compared with BBB, elderly individuals (≥60 years old) who received the BBM vaccination regimen display higher levels of neutralizing antibodies against the Wuhan and Delta strains along with a higher boost in immunoglobulin G memory B cells, particularly against the Omicron variant. Circulating T helper type 1(Th1), Th2, Th17, and T follicular helper responses were also increased in elderly individuals given the BBM regimen. While mRNA vaccines increase antibody, T cell, and B cell responses against SARS-CoV-2 1 month after receiving the third dose booster, the efficacy of the booster vaccine strategies may vary depending on age group and regimen combination.

Medical Nutrition Therapy Provided by Dietitians is Effective and Saves Healthcare Costs in the Management of Adults with Dyslipidemia.

PURPOSE OF REVIEW: Referral to nutrition care providers in the USA such as registered dietitian nutritionists (RDNs) for medical nutrition therapy (MNT) remains low. We summarize research on the effectiveness of MNT provided by dietitians versus usual care in the management of adults with dyslipidemia. Improvements in lipids/lipoproteins were examined. If reported, blood pressure (BP), fasting blood glucose (FBG) glycated hemoglobin (A1c), body mass index (BMI), and cost outcomes were also examined. RECENT FINDINGS: The synthesis of three systematic reviews included thirty randomized controlled trials. Multiple MNT visits (3-6) provided by dietitians, compared with usual care, resulted in significant improvements in total cholesterol (mean range: - 4.64 to - 20.84 mg/dl), low-density lipoprotein cholesterol (mean range: - 1.55 to - 11.56 mg/dl), triglycerides (mean range: - 15.9 to - 32.55 mg/dl), SBP (mean range: - 4.7 to - 8.76 mm Hg), BMI (mean: - 0.4 kg/m2), and A1c (- 0.38%). Cost savings from MNT were attributed to a decrease in medication costs and improved quality of life years (QALY). Multiple MNT visits provided by dietitians compared with usual care improved lipids/lipoproteins, BP, A1c, weight status, and QALY with significant cost savings in adults with dyslipidemia and justify a universal nutrition policy for equitable access to MNT.

Ubiquitination of MHC Class II by March-I Regulates Dendritic Cell Fitness.

The expression and turnover of Ag-specific peptide-MHC class II (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to efficiently activate CD4 T cells. Ubiquitination of pMHC-II by the E3 ubiquitin ligase March-I regulates surface expression and survival of pMHC-II in DCs. We now show that despite their high levels of surface pMHC-II, MHC class II (MHC-II) ubiquitination-deficient mouse DCs are functionally defective; they are poor stimulators of naive CD4 T cells and secrete IL-12 in response to LPS stimulation poorly. MHC-II ubiquitination-mutant DC defects are cell intrinsic, and single-cell RNA sequencing demonstrates that these DCs have an altered gene expression signature as compared with wild-type DCs. Curiously, these functional and gene transcription defects are reversed by activating the DCs with LPS. These results show that dysregulation of MHC-II turnover suppresses DC development and function.

US Population Eligibility and Estimated Impact of Semaglutide Treatment on Obesity Prevalence and Cardiovascular Disease Events.

BACKGROUND: Semaglutide 2.4 mg benefits weight loss and reduction of cardiovascular disease (CVD) risk factors in adults with obesity. We estimated the US population eligibility for semaglutide 2.4 mg (based on the weight management indication) and the impact on obesity and CVD events. METHODS: We applied STEP 1 trial eligibility criteria to US adults aged ≥ 18 years in the US National Health and Nutrition Examination Survey (NHANES) 2015-2018 to estimate the US eligible population. Semaglutide weight changes in STEP 1 were applied to estimate the population impact on weight changes and obesity prevalence. We also estimated 10-year CVD risks utilizing the BMI-based Framingham CVD risk scores. The difference in estimated risks with and without semaglutide "treatment" multiplied by the eligible NHANES weighted population represented the estimated "preventable" CVD events. RESULTS: We identified 3999 US adults weighted to an estimated population size of 93.0 million [M] (38% of US adults) who fit STEP 1 eligibility criteria. Applying STEP 1 treatment effects on weight loss resulted in an estimated 69.1% (64.3 M) and 50.5% (47.0 M) showing ≥ 10% and ≥ 15% weight reductions, respectively, translating to a 46.1% (43.0 M) reduction in obesity (BMI ≥ 30 kg/m2) prevalence. Among those without CVD, estimated 10-year CVD risks were 10.15% "before" and 8.34% "after" semaglutide "treatment" reflecting a 1.81% absolute (and 17.8% relative) risk reduction translating to 1.50 million preventable CVD events over 10 years. CONCLUSION: Semaglutide treatment in eligible US adults may substantially reduce obesity prevalence and CVD events, which may dramatically impact associated healthcare costs.

Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop.

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.

Prevalence of statin intolerance: a meta-analysis.

AIMS: Statin intolerance (SI) represents a significant public health problem for which precise estimates of prevalence are needed. Statin intolerance remains an important clinical challenge, and it is associated with an increased risk of cardiovascular events. This meta-analysis estimates the overall prevalence of SI, the prevalence according to different diagnostic criteria and in different disease settings, and identifies possible risk factors/conditions that might increase the risk of SI. METHODS AND RESULTS: We searched several databases up to 31 May 2021, for studies that reported the prevalence of SI. The primary endpoint was overall prevalence and prevalence according to a range of diagnostic criteria [National Lipid Association (NLA), International Lipid Expert Panel (ILEP), and European Atherosclerosis Society (EAS)] and in different disease settings. The secondary endpoint was to identify possible risk factors for SI. A random-effects model was applied to estimate the overall pooled prevalence. A total of 176 studies [112 randomized controlled trials (RCTs); 64 cohort studies] with 4 143 517 patients were ultimately included in the analysis. The overall prevalence of SI was 9.1% (95% confidence interval 8.0-10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria [7.0% (6.0-8.0%), 6.7% (5.0-8.0%), 5.9% (4.0-7.0%), respectively]. The prevalence of SI in RCTs was significantly lower compared with cohort studies [4.9% (4.0-6.0%) vs. 17% (14-19%)]. The prevalence of SI in studies including both primary and secondary prevention patients was much higher than when primary or secondary prevention patients were analysed separately [18% (14-21%), 8.2% (6.0-10%), 9.1% (6.0-11%), respectively]. Statin lipid solubility did not affect the prevalence of SI [4.0% (2.0-5.0%) vs. 5.0% (4.0-6.0%)]. Age [odds ratio (OR) 1.33, P = 0.04], female gender (OR 1.47, P = 0.007), Asian and Black race (P < 0.05 for both), obesity (OR 1.30, P = 0.02), diabetes mellitus (OR 1.26, P = 0.02), hypothyroidism (OR 1.37, P = 0.01), chronic liver, and renal failure (P < 0.05 for both) were significantly associated with SI in the meta-regression model. Antiarrhythmic agents, calcium channel blockers, alcohol use, and increased statin dose were also associated with a higher risk of SI. CONCLUSION: Based on the present analysis of >4 million patients, the prevalence of SI is low when diagnosed according to international definitions. These results support the concept that the prevalence of complete SI might often be overestimated and highlight the need for the careful assessment of patients with potential symptoms related to SI.

NF-κB Signaling Modulates miR-452-5p and miR-335-5p Expression to Functionally Decrease Epithelial Ovarian Cancer Progression in Tumor-Initiating Cells.

Epithelial ovarian cancer (EOC) remains the fifth leading cause of cancer-related death in women worldwide, partly due to the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. We previously described a role for the NF-κB pathway in promoting TIC chemoresistance and survival through NF-κB transcription factors (TFs) RelA and RelB, which regulate genes important for the inflammatory response and those associated with cancer, including microRNAs (miRNAs). We hypothesized that NF-κB signaling differentially regulates miRNA expression through RelA and RelB to support TIC persistence. Inducible shRNA was stably expressed in OV90 cells to knockdown RELA or RELB; miR-seq analyses identified differentially expressed miRNAs hsa-miR-452-5p and hsa-miR-335-5p in cells grown in TIC versus adherent conditions. We validated the miR-seq findings via qPCR in TIC or adherent conditions with RELA or RELB knocked-down. We confirmed decreased expression of hsa-miR-452-5p when either RELA or RELB were depleted and increased expression of hsa-miR-335-5p when RELA was depleted. Either inhibiting miR-452-5p or mimicking miR-335-5p functionally decreased the stem-like potential of the TICs. These results highlight a novel role of NF-κB TFs in modulating miRNA expression in EOC cells, thus opening a better understanding toward preventing recurrence of EOC.

Hydroxylation Regiochemistry Is Robust to Active Site Mutations in Cytochrome P450cam (CYP101A1).

Cytochrome P450cam (CYP101A1) catalyzes the hydroxylation of d-camphor by molecular oxygen. The enzyme-catalyzed hydroxylation exhibits a high degree of regioselectivity and stereoselectivity, with a single major product, d-5-exo-hydroxycamphor, suggesting that the substrate is oriented to facilitate this specificity. In previous work, we used an elastic network model and perturbation response scanning to show that normal deformation modes of the enzyme structure are highly responsive not only to the presence of a substrate but also to the substrate orientation. This work examines the effects of mutations near the active site on substrate localization and orientation. The investigated mutations were designed to promote a change in substrate orientation and/or location that might give rise to different hydroxylation products, while maintaining the same carbon and oxygen atom balances as in the wild type (WT) enzyme. Computational experiments and parallel in vitro site-directed mutations of CYP101A1 were used to examine reaction products and enzyme activity. 1H-15N TROSY-HSQC correlation maps were used to compare the computational results with detectable perturbations in the enzyme structure and dynamics. We found that all of the mutant enzymes retained the same regio- and stereospecificity of hydroxylation as the WT enzyme, with varying degrees of efficiency, which suggests that large portions of the enzyme have been subjected to evolutionary pressure to arrive at the appropriate sequence-structure combination for efficient 5-exo hydroxylation of camphor.

Survival Impact of Variant Histology Diagnosis in Upper Tract Urothelial Carcinoma.

PURPOSE: Little is known regarding the prognostic implications of variant histology in upper tract urothelial carcinoma (UTUC). We sought to evaluate the impact of variant histology UTUC on patient survival outcomes at our institution. MATERIALS AND METHODS: We identified 705 patients who underwent nephroureterectomy for UTUC at our institution between January 1995 and December 2018. We tested the association between variant histology and cancer-specific survival (CSS) and overall survival (OS) using separate multivariable Cox models after adjusting for pathological stage. RESULTS: Forty-seven patients (6.7%) had variant histology, with prevalence increasing over time (p=0.003). Other demographic and surgical characteristics were similar between variant histology and pure urothelial carcinoma groups. While patients with variant histology were more likely to receive neoadjuvant chemotherapy (38% vs 15%, p <0.001), they were also more likely to have a higher pathological T stage (p <0.001). Variant histology was associated with significantly worse CSS (HR: 2.14; 95% CI 1.33, 3.44; p=0.002) and OS (HR: 1.74; 95% CI 1.15, 2.63; p=0.008). After adjusting for pathological T stage, variant histology was not significantly associated with CSS (HR: 1.17; 95% CI 0.72, 1.89; p=0.5) or OS (HR: 1.20; 95% CI 0.79, 1.84; p=0.4). CONCLUSIONS: Variant histology UTUC is associated with advanced stage and poor survival, and could serve as a useful biomarker for high-risk disease when pathological stage is unknown. However, the inferior CSS and OS with variant histology can be explained by the higher tumor stage on nephroureterectomy. Thus, finding variant histology on surgical pathology does not provide additional prognostic information beyond stage.

Vasoplegia Following Orthotopic Heart Transplantation: Prevalence, Predictors and Clinical Outcomes.

BACKGROUND: Patients undergoing heart transplant are at high risk for postoperative vasoplegia. Despite its frequency and association with poor clinical outcomes, there remains no consensus definition for vasoplegia, and the predisposing risk factors for vasoplegia remain unclear. Accordingly, the aim of this study was to evaluate the prevalence, predictors, and clinical outcomes associated with vasoplegia in a contemporary cohort of patients undergoing heart transplantation. METHODS: This was a retrospective cohort study of patients undergoing heart transplantation from January 2015 to December 2019. A binary definition of vasoplegia of a cardiac index of 2.5 L/min/m2 or greater and requirement for norepinephrine (≥5 µg/min), epinephrine (≥4 µg/min), or vasopressin (≥1 unit/h) to maintain a mean arterial blood pressure of 65 mm Hg, for 6 consecutive hours during the first 48 hours postoperatively, was used in determining prevalence. Given the relatively low threshold for the binary definition of vasoplegia, patients were divided into tertiles based on their cumulative vasopressor requirement in the 48 hours following transplant. Outcomes included all-cause mortality, intubation time, intensive care unit length of stay, and length of total hospitalization. RESULTS: After exclusion of patients with primary cardiogenic shock, major bleeding, or overt sepsis, data were collected on 95 eligible patients. By binary definition, vasoplegia incidence was 66.3%. We separately stratified by actual vasopressor requirement tertile (high, intermediate, low). Stratified by tertile, patients with vasoplegia were older (52.7 ± 10.2 vs 46.8 ± 12.7 vs 44.4 ± 11.3 years, P = .02), with higher rates of chronic kidney disease (18.8% vs 32.3% vs 3.1%, P = .01) and were more likely to have been transplanted from left ventricular assist device support (n = 42) (62.5% vs 32.3% vs 37.5%, P = .03). Cardiopulmonary bypass time was prolonged in those that developed vasoplegia (155 min [interquartile range 135-193] vs 131 min [interquartile range 117-152] vs 116 min [interquartile range 102-155], P = .003). Intubation time and length of intensive care unit and hospital stay were significantly increased in those that developed vasoplegia; however, this difference did not translate to a significant increase in all-cause mortality at 30 days or 1 year. CONCLUSIONS: Vasoplegia occurs at a high rate after heart transplantation. Older age, chronic kidney disease, mechanical circulatory support, and prolonged bypass time are all associated with vasoplegia; however, this study did not demonstrate an associated increase in all-cause mortality LAY SUMMARY: Patients undergoing heart transplantation are at high risk of vasoplegia, a condition defined by low blood pressure despite normal heart function. We found that vasoplegia was common after heart transplant, occurring in 60%-70% of patients after heart transplant after excluding those with other causes for low blood pressure. Factors implicated included age, poor kidney function, prolonged cardiopulmonary bypass time and preoperative left ventricular assist device support. We found no increased risk of death in patients with vasoplegia despite longer lengths of stay in intensive care and in hospital.

Evolution of Coronary Calcium Screening for Assessment of Atherosclerotic Cardiovascular Disease Risk and Role in Preventive Cardiology.

PURPOSE OF REVIEW: Coronary artery calcium (CAC) is an important measure of subclinical atherosclerosis and strongly predicts atherosclerotic cardiovascular disease (ASCVD) outcomes. The purpose of this review is to discuss the key studies that have helped to establish its role as an important screening tool and its place in preventive cardiology. RECENT FINDINGS: Epidemiologic studies document a strong relation of age, race/ethnicity, and risk factors with the prevalence and extent of CAC. Large-scale registry and prospective investigations show CAC to be the strongest subclinical disease predictor of ASCVD outcomes, with higher CAC scores associated with successively higher risks and those with a CAC score of 0 having a long-term "warranty" against having events. Moreover, CAC is associated with greater initiation of preventive health behaviors and therapy. Current US guidelines utilize CAC to inform the treatment decision for statin therapy. Further study is underway to document whether CAC screening will ultimately improve clinical outcomes. CAC is well established as the most important subclinical cardiovascular disease measure for prediction of future ASCVD outcomes and can be used for informing the treatment decision for preventive therapies.