Chromatin-Modifying Enzymes in T Cell Development.

T cell development involves stepwise progression through defined stages that give rise to multiple T cell subtypes, and this is accompanied by the establishment of stage-specific gene expression. Changes in chromatin accessibility and chromatin modifications accompany changes in gene expression during T cell development. Chromatin-modifying enzymes that add or reverse covalent modifications to DNA and histones have a critical role in the dynamic regulation of gene expression throughout T cell development. As each chromatin-modifying enzyme has multiple family members that are typically all coexpressed during T cell development, their function is sometimes revealed only when two related enzymes are concurrently deleted. This work has also revealed that the biological effects of these enzymes often involve regulation of a limited set of targets. The growing diversity in the types and sites of modification, as well as the potential for a single enzyme to catalyze multiple modifications, is also highlighted.

Regulation of intestinal immunity and tissue repair by enteric glia.

Tissue maintenance and repair depend on the integrated activity of multiple cell types1. Whereas the contributions of epithelial2,3, immune4,5 and stromal cells6,7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease8. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ-EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.

An allelic series at the EDNRB2 locus controls diverse piebalding patterns in the domestic pigeon.

Variation in pigment patterns within and among vertebrate species reflects underlying changes in cell migration and function that can impact health, reproductive success, and survival. The domestic pigeon (Columba livia) is an exceptional model for understanding the genetic changes that give rise to diverse pigment patterns, as selective breeding has given rise to hundreds of breeds with extensive variation in plumage color and pattern. Here, we map the genetic architecture of a suite of pigmentation phenotypes known as piebalding. Piebalding is characterized by patches of pigmented and non-pigmented feathers, and these plumage patterns are often breed-specific and stable across generations. Using a combination of quantitative trait locus mapping in F2 laboratory crosses and genome-wide association analysis, we identify a locus associated with piebalding across many pigeon breeds. This shared locus harbors a candidate gene, EDNRB2, that is a known regulator of pigment cell migration, proliferation, and survival. We discover multiple distinct haplotypes at the EDNRB2 locus in piebald pigeons, which include a mix of protein-coding, noncoding, and structural variants that are associated with depigmentation in specific plumage regions. These results identify a role for EDNRB2 in pigment patterning in the domestic pigeon, and highlight how repeated selection at a single locus can generate a diverse array of stable and heritable pigment patterns.

Long-Term Mortality in Patients With Severe Hypercholesterolemia Phenotype From a Racial and Ethnically Diverse US Cohort.

BACKGROUND: Tools for mortality prediction in patients with the severe hypercholesterolemia phenotype (low-density lipoprotein cholesterol ≥190 mg/dL) are limited and restricted to specific racial and ethnic cohorts. We sought to evaluate the predictors of long-term mortality in a large racially and ethnically diverse US patient cohort with low-density lipoprotein cholesterol ≥190 mg/dL. METHODS: We conducted a retrospective analysis of all patients with a low-density lipoprotein cholesterol ≥190 mg/dL seeking care at Montefiore from 2010 through 2020. Patients <18 years of age or with previous malignancy were excluded. The primary end point was all-cause mortality. Analyses were stratified by age, sex, and race and ethnicity. Patients were stratified by primary and secondary prevention. Cox regression analyses were used to adjust for demographic, clinical, and treatment variables. RESULTS: A total of 18 740 patients were included (37% non-Hispanic Black, 30% Hispanic, 12% non-Hispanic White, and 2% non-Hispanic Asian patients). The mean age was 53.9 years, and median follow-up was 5.2 years. Both high-density lipoprotein cholesterol and body mass index extremes were associated with higher mortality in univariate analyses. In adjusted models, higher low-density lipoprotein cholesterol and triglyceride levels were associated with an increased 9-year mortality risk (adjusted hazard ratio [HR], 1.08 [95% CI, 1.05-1.11] and 1.04 [95% CI, 1.02-1.06] per 20-mg/dL increase, respectively). Clinical factors associated with higher mortality included male sex (adjusted HR, 1.31 [95% CI, 1.08-1.58]), older age (adjusted HR, 1.19 per 5-year increase [95% CI, 1.15-1.23]), hypertension (adjusted HR, 2.01 [95% CI, 1.57-2.57]), chronic kidney disease (adjusted HR, 1.68 [95% CI, 1.36-2.09]), diabetes (adjusted HR, 1.79 [95% CI, 1.50-2.15]), heart failure (adjusted HR, 1.51 [95% CI, 1.16-1.95]), myocardial infarction (adjusted HR, 1.41 [95% CI, 1.05-1.90]), and body mass index <20 kg/m2 (adjusted HR, 3.36 [95% CI, 2.29-4.93]). A significant survival benefit was conferred by lipid-lowering therapy (adjusted HR, 0.57 [95% CI, 0.42-0.77]). In the primary prevention group, high-density lipoprotein cholesterol <40 mg/dL was independently associated with higher mortality (adjusted HR, 1.49 [95% CI, 1.06-2.09]). Temporal trend analyses showed a reduction in statin use over time (P<0.001). In the most recent time period (2019-2020), 56% of patients on primary prevention and 85% of those on secondary prevention were on statin therapy. CONCLUSIONS: In a large, diverse cohort of US patients with the severe hypercholesterolemia phenotype, we identified several patient characteristics associated with increased 9-year all-cause mortality and observed a decrease in statin use over time, in particular for primary prevention. Our results support efforts geared toward early recognition and consistent treatment for patients with severe hypercholesterolemia.

Immune-Mediated Inflammatory Diseases, Dyslipidemia, and Cardiovascular Risk: A Complex Interplay.

Individuals with autoimmune inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, are at increased risk for cardiovascular disease. While these diseases share common features of systemic inflammation, the impact of individual autoimmune inflammatory conditions on circulating lipids and lipoproteins varies by specific disease, disease activity, and the immune-suppressing medications used to treat these conditions. A common feature observed in many autoimmune inflammatory diseases is the development of a proatherogenic dyslipidemic state, characterized by dysfunctional HDLs (high-density lipoproteins) and increased oxidation of LDLs (low-density lipoproteins). Various disease-modifying antirheumatic drugs also have complex and variable effects on lipids, and it is critical to take this into consideration when evaluating lipid-related risk in individuals with immune-mediated inflammatory conditions. This review aims to critically evaluate the current understanding of the relationship between immune-mediated inflammatory diseases and dyslipidemia, the underlying mechanisms contributing to atherogenesis, and the impact of various pharmacotherapies on lipid profiles and cardiovascular risk. We also discuss the role of lipid-lowering therapies, particularly statins, in managing residual risk in this high-risk population and explore the potential of emerging therapies with complementary anti-inflammatory and lipid-lowering effects.

Chromatin interaction maps identify Wnt responsive cis-regulatory elements coordinating Paupar-Pax6 expression in neuronal cells.

Central nervous system-expressed long non-coding RNAs (lncRNAs) are often located in the genome close to protein coding genes involved in transcriptional control. Such lncRNA-protein coding gene pairs are frequently temporally and spatially co-expressed in the nervous system and are predicted to act together to regulate neuronal development and function. Although some of these lncRNAs also bind and modulate the activity of the encoded transcription factors, the regulatory mechanisms controlling co-expression of neighbouring lncRNA-protein coding genes remain unclear. Here, we used high resolution NG Capture-C to map the cis-regulatory interaction landscape of the key neuro-developmental Paupar-Pax6 lncRNA-mRNA locus. The results define chromatin architecture changes associated with high Paupar-Pax6 expression in neurons and identify both promoter selective as well as shared cis-regulatory-promoter interactions involved in regulating Paupar-Pax6 co-expression. We discovered that the TCF7L2 transcription factor, a regulator of chromatin architecture and major effector of the Wnt signalling pathway, binds to a subset of these candidate cis-regulatory elements to coordinate Paupar and Pax6 co-expression. We describe distinct roles for Paupar in Pax6 expression control and show that the Paupar DNA locus contains a TCF7L2 bound transcriptional silencer whilst the Paupar transcript can act as an activator of Pax6. Our work provides important insights into the chromatin interactions, signalling pathways and transcription factors controlling co-expression of adjacent lncRNAs and protein coding genes in the brain.

The Use and Impact of a Decision Support Tool for Appendicitis Treatment.

OBJECTIVE: Since introducing new and alternative treatment options may increase decisional conflict, we aimed to describe the use of the decision support tool (DST) and its impact on treatment preference and decisional conflict. BACKGROUND: For the treatment of appendicitis, antibiotics are an effective alternative to appendectomy, with both approaches associated with a different set of risks (eg, recurrence vs surgical complications) and benefits (eg, more rapid return to work vs decreased chance of readmission). Patients often have limited knowledge of these treatment options, and DSTs that include video-based educational materials and questions to elicit patient preferences about outcomes may be helpful. Concurrent with the Comparing Outcomes of Drugs and Appendectomy trials, our group developed a DST for appendicitis treatment ( www.appyornot.org ). METHODS: A retrospective cohort including people who self-reported current appendicitis and used the AppyOrNot DST between 2021 and 2023. Treatment preferences before and after the use of the DST, demographic information, and Ottawa Decisional Conflict Scale (DCS) were reported after completing the DST. RESULTS: A total of 8243 people from 66 countries and all 50 U.S. states accessed the DST. Before the DST, 14% had a strong preference for antibiotics and 31% for appendectomy, with 55% undecided. After using the DST, the proportion in the undecided category decreased to 49% ( P < 0.0001). Of those who completed the Ottawa Decisional Conflict Score (DCS; n = 356), 52% reported the lowest level of decisional conflict (<25) after using the DST; 43% had a DCS score of 25 to 50, 5.1% had a DCS score of >50 and 2.5% had and DCS score of >75. CONCLUSIONS: The publicly available DST appyornot.org reduced the proportion that was undecided about which treatment they favored and had a modest influence on those with strong treatment preferences. Decisional conflict was not common after use. The use of this DST is now a component of a nationwide implementation program aimed at improving the way surgeons share information about appendicitis treatment options. If its use can be successfully implemented, this may be a model for improving communication about treatment for patients experiencing emergency health conditions.

Failure Mode Effects Analysis of Re-triage of Injured Patients to Receiving High-Level Illinois Trauma Centers.

OBJECTIVE: This study identified failures in emergency inter-hospital transfer, or re-triage, at high-level trauma centers receiving severely injured patients. SUMMARY BACKGROUND DATA: The re-triage process averages four hours despite the fact timely re-triage within two hours mitigates injury-associated mortality. Non-trauma and low-level trauma centers reported most critical failures were in finding an accepting high-level trauma center. Critical failures at high-level trauma centers have not been assessed. METHODS: This was an observational cross-sectional study at nine high-level adult trauma centers and three high-level pediatric trauma centers. Failure Modes Effects Analysis (FMEA) of the re-triage process was conducted in four phases. Phase 1 purposively sampled trauma coordinators followed by snowball sampling of clinicians, operations, and leadership to ensure representative participation. Phase 2 mapped each re-triage step. Phase 3 identified failures at each step. Phase 4 scored each failure on impact, frequency, and safeguards for detection. Standardized rubrics were used in Phase 4 to rate each failure's impact (I), frequency (F), and safeguard for detection (S) to calculate their Risk Priority Number (RPN) (I x F x S). Failures were rank ordered for criticality. RESULTS: A total of 64 trauma coordinators, surgeons, emergency medicine physicians, nurses, operations and quality managers across twelve high-level trauma centers participated. There were 178failures identified at adult and pediatric high-level trauma centers. The most critical failures were: Insufficient trained transport staff (RPN=648); Issues transmitting imaging from sending to receiving centers (RPN=400); Incomplete exchange of clinical information(RPN=384). CONCLUSIONS: The most critical failures were limited transportation and incomplete exchange of clinical, radiological and arrival timing information. Further investigation of these failures that includes several regions is needed to determine the reproducibility of these findings.

Achievement of LDL-C <55 mg/dL among US adults: Findings from the cvMOBIUS2 registry.

BACKGROUND: Reflecting clinical trial data showing improved outcomes with lower LDL-C levels, guidelines across the globe are increasingly recommending a goal of LDL-C <55 mg/dL in persons with atherosclerotic cardiovascular disease (ASCVD). What proportion of patients with ASCVD are already meeting those goals in the US remains understudied. METHODS: Using electronic health record data from 8 large US health systems, we evaluated lipid-lowering therapy (LLT), LDL-C levels, and factors associated with an LDL-C <55 mg/dL in persons with ASCVD treated between 1/1/2021-12/31/2021. Multivariable modeling was used to evaluate factors associated with achievement of an LDL-C <55 mg/dL. RESULTS: Among 167,899 eligible patients, 22.6% (38,016) had an LDL-C <55 mg/dL. While 76.1% of individuals overall were on a statin, only 38.2% were on a high-intensity statin, 5.9% were on ezetimibe, and 1.7% were on a PCSK9i monoclonal antibody (mAb). Factors associated with lower likelihood of achieving an LDL-C <55 mg/dL included: younger age (odds ratio [OR] 0.91 per 10y), female sex (OR 0.69), Black race (OR 0.76), and noncoronary artery disease forms of ASCVD including peripheral artery disease (OR 0.72) and cerebrovascular disease (OR 0.85), while high-intensity statin use was associated with increased odds of LDL-C <55 mg/dL (OR 1.55). Combination therapy (statin+ezetimibe or statin+PCSK9i mAb) was rare (4.4% and 0.5%, respectively) and was associated with higher odds of an LDL-C <55 mg/dL (OR 1.39 and 3.13, respectively). CONCLUSION: Less than a quarter of US patients with ASCVD in community practice are already achieving an LDL-C <55 mg/dL. Marked increases in utilization of both high intensity statins and combination therapy with non-statin therapy will be needed to achieve LDL-C levels <55 mg/dL at the population level in secondary prevention.

The Role of Sleep in Cardiovascular Disease.

PURPOSE OF REVIEW: Sleep is an important component of cardiovascular (CV) health. This review summarizes the complex relationship between sleep and CV disease (CVD). Additionally, we describe the data supporting the treatment of sleep disturbances in preventing and treating CVD. RECENT FINDINGS: Recent guidelines recommend screening for obstructive sleep apnea in patients with atrial fibrillation. New data continues to demonstrate the importance of sleep quality and duration for CV health. There is a complex bidirectional relationship between sleep health and CVD. Sleep disturbances have systemic effects that contribute to the development of CVD, including hypertension, coronary artery disease, heart failure, and arrhythmias. Additionally, CVD contributes to the development of sleep disturbances. However, more data are needed to support the role of screening for and treatment of sleep disorders for the prevention of CVD.

Efficacy of Aspirin for primary prevention among adults with high-risk type 2 diabetes in the ACCORD trial.

AIM: To assess the efficacy of aspirin use for primary prevention of cardiovascular disease (CVD) with incident atherosclerotic CVD and mortality in high-risk type 2 diabetes. METHODS: In this post hoc analysis, we included participants in the ACCORD trial without CVD at baseline. The association between aspirin use and the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular [CV] death) and all-cause mortality was evaluated using Cox proportional hazard analysis adjusting for demographics, CV risk factors and comorbidities. RESULTS: Eligible participants (n = 6330) were aged 62.8 ± 5.9 years at baseline, 43.8% of the participants were female, and 3026 (47.8%) used aspirin. Over a median (interquartile range) follow-up of 4.9 (4.1-5.7) years, the number (%) of primary outcome and all-cause mortality events in those who used aspirin (vs. those who did not), was 196 (6.5) versus 229 (6.9) and 146 (4.8) versus 147 (4.5), respectively. The adjusted hazard ratios (95% confidence interval) associated with aspirin use for the primary outcome and all-cause mortality were 0.94 (0.77-1.14) and 1.08 (0.85-1.36), respectively. CONCLUSION: In high-risk individuals with type 2 diabetes, the use of aspirin for primary prevention was not associated with a decreased risk of incident CVD or all-cause mortality.

Serum bile acid profiles are associated with heart failure with preserved ejection fraction in patients with metabolic dysfunction-associated fatty liver disease: An exploratory study.

AIM: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status. CONCLUSIONS: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD.

Worldwide prevalence of chagas cardiomyopathy-an analysis from the global burden of disease dataset.

PURPOSE: The worldwide prevalence of Chagas Cardiomyopathy (CCM) as well as the trends in the prevalence of CCM over time have not been well characterized. METHODS: An analysis of the Global Burden of Disease (GBD) data from 1990 to 2019 was conducted to assess the burden of CCM. This study focused on determining the prevalence of CCM, along with its age-standardized prevalence rate (ASR) per 1,00,000 people, considering various patient demographics and geographical regions as defined in the GBD. Additionally, the study examined the temporal trends over this 30-year period by calculating the estimated annual percentage change (EAPC) in CCM prevalence for the global population and specific subgroups. RESULTS: Worldwide, the GBD reported 220,166 individuals with CCM in 1990 and 2,83,236 individuals in 2019, with a decline in the ASR from 5.23 (3.34-7.47) to 3.42 (2.2-4.91) per 1,00,000 individuals during that period. In 2019, the prevalence was highest in individuals over age 70 and in males compared to females. Among available geographic classifications in 2019, Latin American regions had the highest rates (ASR of 39.49-61.15/1,00,000), while high income North American and Western European regions had the lowest rates (ASRs of 0.67 and 0.34/1,00,000, respectively). Between 1990 and 2019, the worldwide prevalence of CCM per 1,00,000 decreased (EAPC of -0.35, -0.37 to -0.32), with similar trends among most regions and subgroups. CONCLUSION: This analysis of the GBD data reveals both global and country-specific patterns in the prevalence and trends of CCM. Notably, CCM shows the highest prevalence in Latin American countries, although it's also significantly present in regions beyond Latin America. Notably, the global age-standardized rate of CCM is on the decline, suggesting improvements in healthcare strategies or lifestyle changes across the world.

Cutting Edge: Enhanced Antitumor Immunity in ST8Sia6 Knockout Mice.

Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.

Impact of Statin Therapy on Diabetes Incidence: Implications for Primary Prevention.

PURPOSE OF REVIEW: The present review aims to summarize current evidence, explore underlying mechanisms, and help guide clinicians regarding statin therapy and diabetes risk in primary prevention. RECENT FINDINGS: The observational and genetic epidemiology, as well as evidence from randomized controlled trials and meta-analyses, illustrate a modest, dose-dependent increase in risk of diabetes from statin therapy. Risk of new onset diabetes from statins appears to be greatest in those near the diagnostic threshold for diabetes or with diabetes risk factors prior to statin initiation. The risk of incident diabetes is vastly offset by the cardiovascular protection offered from statin therapy and should not deter guideline recommended statin initiation in primary prevention.

Circulating ketone bodies and cardiovascular outcomes: the MESA study.

AIMS: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD). METHODS AND RESULTS: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]. CONCLUSION: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment.

Effect of vigorous-intensity physical activity on incident cognitive impairment in high-risk hypertension.

INTRODUCTION: We investigated the effect vigorous physical activity (VPA) on the risk of incident mild cognitive impairment (MCI) and probable dementia among individuals with high-risk hypertension. METHODS: Baseline self-reported frequency of VPA was categorized into low VPA (<1 session/week), and high VPA (≥1 session/week). We used multivariate Cox regression analysis to examine the association of VPA categories with incident MCI and probable dementia events. RESULTS: Participants in the high VPA category, compared with low VPA, experienced lower events rates (per 1000 person-years) of MCI (13.9 vs 19.7), probable dementia (6.3 vs 9.0), and MCI/probable dementia (18.5 vs 25.8). In the multivariate Cox regression model, high VPA, compared with low VPA, was associated with lower risk of MCI, probable dementia, and MCI/probable dementia (HR [95% CI]: 0.81 [0.68-0.97], 0.80 [0.63-1.03], and 0.82 [0.70-0.96]), respectively. DISCUSSION: This study provides evidence that VPA may preserve cognitive function in high-risk patients with hypertension. HIGHLIGHTS: Hypertension is associated with an increased risk of cognitive impairment Physical activity (PA) is associated with a lower risk of decline in cognition The effect of ≥1 sessions of vigorous-intensity PA (VPA) per week was assessed This analysis included SPRINT MIND trial participants with high-risk hypertension ≥1 VPA sessions/week was associated with lower risk of future cognitive impairment.

Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS: APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).

Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments.

Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

Closing the Gaps in Care of Dyslipidemia: Revolutionizing Management with Digital Health and Innovative Care Models.

Although great progress has been made in the diagnostic and treatment options for dyslipidemias, unawareness, underdiagnosis and undertreatment of these disorders remain a significant global health concern. Growth in digital applications and newer models of care provide novel tools to improve the management of chronic conditions such as dyslipidemia. In this review, we discuss the evolving landscape of lipid management in the 21st century, current treatment gaps and possible solutions through digital health and new models of care. Our discussion begins with the history and development of value-based care and the national establishment of quality metrics for various chronic conditions. These concepts on the level of healthcare policy not only inform reimbursements but also define the standard of care. Next, we consider the advances in atherosclerotic cardiovascular disease risk score calculators as well as evolving imaging modalities. The impact and growth of digital health, ranging from telehealth visits to online platforms and mobile applications, will also be explored. We then evaluate the ways in which machine learning and artificial intelligence-driven algorithms are being utilized to address gaps in lipid management. From an organizational perspective, we trace the redesign of medical practices to incorporate a multidisciplinary team model of care, recognizing that atherosclerotic cardiovascular disease risk is multifaceted and requires a comprehensive approach. Finally, we anticipate the future of dyslipidemia management, assessing the many ways in which atherosclerotic cardiovascular disease burden can be reduced on a population-wide scale.