Alterations in the spatiotemporal expression of the chemokine receptor CXCR4 in endothelial cells cause failure of hierarchical vascular branching.

The C-X-C chemokine receptor CXCR4 and its ligand CXCL12 play an important role in organ-specific vascular branching morphogenesis. CXCR4 is preferentially expressed by arterial endothelial cells, and local secretion of CXCL12 determines the organotypic pattern of CXCR4+ arterial branching. Previous loss-of-function studies clearly demonstrated that CXCL12-CXCR4 signaling is necessary for proper arterial branching in the developing organs such as the skin and heart. To further understand the role of CXCL12-CXCR4 signaling in organ-specific vascular development, we generated a mouse model carrying the Cre recombinase-inducible Cxcr4 transgene. Endothelial cell-specific Cxcr4 gain-of-function embryos exhibited defective vascular remodeling and formation of a hierarchical vascular branching network in the developing skin and heart. Ectopic expression of CXCR4 in venous endothelial cells, but not in lymphatic endothelial cells, caused blood-filled, enlarged lymphatic vascular phenotypes, accompanied by edema. These data suggest that CXCR4 expression is tightly regulated in endothelial cells for appropriate vascular development in an organ-specific manner.

Leveraging Healthcare System Data to Identify High-Risk Dyslipidemia Patients.

PURPOSE OF REVIEW: While randomized controlled trials have historically served as the gold standard for shaping guideline recommendations, real-world data are increasingly being used to inform clinical decision-making. We describe ways in which healthcare systems are generating real-world data related to dyslipidemia and how these data are being leveraged to improve patient care. RECENT FINDINGS: The electronic medical record has emerged as a major source of clinical data, which alongside claims and pharmacy dispending data is enabling healthcare systems the ability to identify care gaps (underdiagnosis and undertreatment) in patients with dyslipidemia. Availability of this data also allows healthcare systems the ability to test and deliver interventions at the point-of-care. Real-world data possess great potential as a complement to randomized controlled trials. Healthcare systems are uniquely positioned to not only define care gaps and areas of opportunity, but to also to leverage tools (e.g., clinical decision support, case identification) aimed at closing them.

Metabolic syndrome and its factors are associated with noncalcified coronary burden in psoriasis: An observational cohort study.

BACKGROUND: Psoriasis is associated with a heightened risk of cardiovascular disease and higher prevalence of metabolic syndrome. OBJECTIVE: Investigate the effect of metabolic syndrome and its factors on early coronary artery disease assessed as noncalcified coronary burden by coronary computed tomography angiography in psoriasis. METHODS: This cross-sectional study consisted of 260 participants with psoriasis and coronary computed tomography angiography characterization. Metabolic syndrome was defined according to the harmonized International Diabetes Federation criteria. RESULTS: Of the 260 participants, 80 had metabolic syndrome (31%). The metabolic syndrome group had a higher burden of cardiometabolic disease, systemic inflammation, noncalcified coronary burden, and high-risk coronary plaque. After adjusting for Framingham risk score, lipid-lowering therapy, and biologic use, metabolic syndrome (ß = .31; P < .001) and its individual factors of waist circumference (ß = .33; P < .001), triglyceride levels (ß = .17; P = .005), blood pressure (ß = .18; P = .005), and fasting glucose (ß = .17; P = .009) were significantly associated with noncalcified coronary burden. After adjusting for all other metabolic syndrome factors, blood pressure and waist circumference remained significantly associated with noncalcified coronary burden. LIMITATIONS: Observational nature with limited ability to control for confounders. CONCLUSIONS: In psoriasis, individuals with metabolic syndrome had more cardiovascular disease risk factors, systemic inflammation, and noncalcified coronary burden. Efforts to increase metabolic syndrome awareness in psoriasis should be undertaken to reduce the heightened cardiovascular disease risk.

Association Between Oxidation-Modified Lipoproteins and Coronary Plaque in Psoriasis.

RATIONALE: Psoriasis is a systemic inflammatory skin disease associated with cardiovascular disease and lipid dysfunction. However, traditional lipid parameters have limited prognostic value, whereas assessing oxidation-modified lipids in this inflammatory driven condition may capture additional risk. Recently, a study showed that psoriasis was associated with increased lipid-rich coronary plaques; therefore, investigating potential relationships with oxidation-modified lipids may speed understanding of increased cardiovascular disease in psoriasis. OBJECTIVE: To understand whether oxidation-modified lipids associate with traditional lipid phenotypes, cardiometabolic disease biomarkers, and total coronary plaque, with focus on noncalcified burden (NCB) by coronary computed tomographic angiography in psoriasis. METHODS AND RESULTS: Psoriasis subjects and controls (n=252) had profiling for oxidation-modified LDL (low-density lipoprotein), HDL (high-density lipoprotein), Lp(a) (lipoprotein[a]), cholesterol efflux capacity, lipoprotein particle size and number by NMR spectroscopy, and PON-1 (paraoxonase-1) activity. Blinded coronary computed tomographic angiography coronary artery disease characterization included total burden, NCB, and dense-calcified burden. Compared with healthy volunteers, psoriasis subjects were older (mean age, 50.1), had increased body mass index, and homeostatic model assessment of insulin resistance. Psoriasis subjects had increase in oxidized Lp(a), Lp(a), and oxidized HDL (oxHDL; P <0.05 for all) with significant association of oxidized LDL (ß=0.10; P=0.020) and oxHDL (ß=-0.11; P=0.007) with NCB. Moreover, psoriasis subjects expressed significantly higher PON-1 (kU/µL) activity compared with healthy volunteers (8.55±3.21 versus 6.24±3.82; P=0.01). Finally, psoriasis treatment was associated with a reduction in oxHDL (U/mL; 203.79±88.40 versus 116.36±85.03; P<0.001) and with a concomitant decrease in NCB at 1 year (1.04±0.44 versus 0.95±0.32; P=0.03). CONCLUSIONS: Traditional lipids did not capture risk of lipid-rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxidized LDL and oxHDL. The PON-1 activity was increased in psoriasis suggesting possible compensatory antioxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.

Identical Twins Discordant for Metopic Craniosynostosis: Evidence of Epigenetic Influences.

Craniosynostosis, or premature fusion of the cranial sutures, occurs in approximately 1 in 2500 live births. The genetic causes and molecular basis of these disorders have greatly expanded over the last 2 decades, with numerous causative and contributory mutations having been identified. The role of fibroblast growth factor receptor (FGFR) mutations in the etiology of certain eponymous forms of craniosynostosis is now well elucidated; the most common syndromes associated with craniosynostosis are Pfeifer (FGFR1, FGFR2), Apert (FGFR2), Crouzon (FGFR2), Saethre-Chotzen (TWIST1), Jackson-Weiss (FGFR2), Greig (GL13), and Muenke (FGFR3) syndromes. Although pathological expression of these mutations often results in bilateral coronal craniosynostosis, single suture fusions (typically unilateral coronal synostosis) or multiple suture craniosynostosis are possible.The majority of patients diagnosed with craniosynostosis lack an identifiable syndrome or genetic mutation. The etiopathogenesis of these "nonsyndromic" forms of craniosynostosis is believed to involve a complex interplay of genetics, epigenetics, and environmental factors. Evaluation of genes implicated in nonsyndromic craniosynostosis has been conflicting; some evidence demonstrates an interplay between genetic and epigenetic influences while others do not. Certain environmental factors such as teratogenic levels of retinoic acid, maternal metabolic and hematologic disorders, and head growth constraint in utero may increase the likelihood of developing craniosynostosis, but these associations are again tenuous.The authors present 1 of 2 genetically confirmed identical twins discordant for metopic craniosynostosis. The implications of this case are clear: epigenetic influences, environmental influences, or both played a role in the development of this premature suture fusion.

Wall-mounted folding chairs to promote resident physician sitting at the hospital bedside.

BACKGROUND: Sitting at the bedside may improve patient-clinician communication; however, many clinicians do not regularly sit during inpatient encounters. OBJECTIVE: To determine the impact of adding wall-mounted folding chairs inside patient rooms, beyond any impact from a resident education campaign, on the patient-reported frequency of sitting at the bedside by internal medicine resident physicians. DESIGN, SETTING, AND PARTICIPANTS: Prospective, controlled pre-post trial between 2019 and 2022 (data collection paused 2020-2021 due to COVID-19) at an academic hospital in Baltimore, Maryland. Folding chairs were installed in two of four internal medicine units and educational activities were delivered equally across all units. MAIN OUTCOME AND MEASURES: Patient-reported frequency of sitting at bedside, assessed as means on Likert-type items with 1 being "never" and 5 being "every single time." We also examined the frequency of other patient-reported communication behaviors. RESULTS: Two hundred fifty six and 206 patients enrolled in the pre and post-intervention periods, respectively. The mean frequency of patient-reported sitting by resident physicians increased from 1.8 (SD 1.2) to 2.3 (1.2) on education-only units (absolute difference 0.48 [95% CI: 0.21-0.75]) and from 2.0 (1.3) to 3.2 (1.4) on units receiving chairs (1.16, [0.87-1.45]). Comparing differences between groups using ordered logistic regression adjusting for clustering within residents, units with added chairs had greater increases in sitting (odds ratio 2.05 [1.10-3.82]), spending enough time at the bedside (2.43 [1.32-4.49]), and checking for understanding (3.04 [1.44-6.39]). Improvements in sitting and other behaviors were sustained on both types of units. CONCLUSIONS: Adding wall-mounted folding chairs may help promote effective patient-clinician communication.

Valve-in-Valve Transcatheter Aortic Valve Replacement During Second Trimester of Pregnancy.

Critical bioprosthetic aortic valve stenosis is a rare finding in the second trimester of pregnancy. We present the case of a successful valve-in-valve transcatheter aortic valve replacement in a 16-weeks-pregnant patient. We describe the significant role of the multidisciplinary heart team during preconception and pregnancy.

Accuracy of 23 Equations for Estimating LDL Cholesterol in a Clinical Laboratory Database of 5,051,467 Patients.

Background: Alternatives to the Friedewald low-density lipoprotein cholesterol (LDL-C) equation have been proposed. Objective: To compare the accuracy of available LDL-C equations with ultracentrifugation measurement. Methods: We used the second harvest of the Very Large Database of Lipids (VLDbL), which is a population-representative convenience sample of adult and pediatric patients (N = 5,051,467) with clinical lipid measurements obtained via the vertical auto profile (VAP) ultracentrifugation method between October 1, 2015 and June 30, 2019. We performed a systematic literature review to identify available LDL-C equations and compared their accuracy according to guideline-based classification. We also compared the equations by their median error versus ultracentrifugation. We evaluated LDL-C equations overall and stratified by age, sex, fasting status, and triglyceride levels, as well as in patients with atherosclerotic cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, and thyroid dysfunction. Results: Analyzing 23 identified LDL-C equations in 5,051,467 patients (mean±SD age, 56±16 years; 53.3% women), the Martin/Hopkins equation most accurately classified LDL-C to the correct category (89.6%), followed by the Sampson (86.3%), Chen (84.4%), Puavilai (84.1%), Delong (83.3%), and Friedewald (83.2%) equations. The other 17 equations were less accurate than Friedewald, with accuracy as low as 35.1%. The median error of equations ranged from -10.8 to 18.7 mg/dL, and was best optimized using the Martin/Hopkins equation (0.3, IQR-1.6 to 2.4 mg/dL). The Martin/Hopkins equation had the highest accuracy after stratifying by age, sex, fasting status, triglyceride levels, and clinical subgroups. In addition, one in five patients who had Friedewald LDL-C <70 mg/dL, and almost half of the patients with Friedewald LDL-C <70 mg/dL and triglyceride levels 150-399 mg/dL, had LDL-C correctly reclassified to >70 mg/dL by the Martin/Hopkins equation. Conclusions: Most proposed alternatives to the Friedewald equation worsen LDL-C accuracy, and their use could introduce unintended disparities in clinical care. The Martin/Hopkins equation demonstrated the highest LDL-C accuracy overall and across subgroups.

Discordance Between Standard Equations for Determination of LDL Cholesterol in Patients With Atherosclerosis.

BACKGROUND: Accurate estimation of low-density lipoprotein cholesterol (LDL-C) is important for guiding cholesterol-lowering therapy. Different methods currently exist to estimate LDL-C. OBJECTIVES: This study sought to assess discordance of estimated LDL-C using the Friedewald, Sampson, and Martin/Hopkins equations. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease and triglyceride (TG) levels of <400 mg/dL between October 1, 2015, and June 30, 2019, were retrospectively analyzed. LDL-C was estimated using the Friedewald, Sampson, and Martin/Hopkins equations. Patients were categorized as concordant if LDL-C was <70 mg/dL with each pairwise comparison of equations and as discordant if LDL-C was <70 mg/dL for the index equation and ≥70 mg/dL for the comparator. RESULTS: The study included 146,106 patients with atherosclerotic cardiovascular disease (mean age: 68 years; 56% male; 91% White). The Martin/Hopkins equation consistently estimated higher LDL-C values than the Friedewald and Sampson equations. Discordance rates were 15% for the Friedewald vs Martin/Hopkins comparison, 9% for the Friedewald vs Sampson comparison, and 7% for the Sampson vs Martin/Hopkins comparison. Discordance increased at lower LDL-C cutpoints and in those with elevated TG levels. Among patients with TG levels of ≥150 mg/dL, a >10 mg/dL difference in LDL-C was present in 67%, 27%, and 23% of patients when comparing the Friedewald vs Martin/Hopkins, Friedewald vs Sampson, and Sampson vs Martin/Hopkins equations, respectively. CONCLUSIONS: Clinically meaningful differences in estimated LDL-C exist among equations, particularly at TG levels of ≥150 mg/dL and/or lower LDL-C levels. Reliance on the Friedewald and Sampson equations may result in the underestimation and undertreatment of LDL-C in those at increased risk.

A simplified approach to identification of risk status in patients with atherosclerotic cardiovascular disease.

OBJECTIVE: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) Blood Cholesterol Guideline recommendation to classify patients with atherosclerotic cardiovascular disease (ASCVD) as very high-risk (VHR) vs not-VHR (NVHR) has important implications for escalation of medical therapy. We aimed to define the prevalence and clinical characteristics of these two groups within a large multi-state healthcare system and develop a simpler means to assist clinicians in identifying VHR patients using classification and regression tree (CART) analysis. METHODS: We performed a retrospective analysis of all patients in a 28-hospital US healthcare system in 2018. ICD-10 codes were used to define the ASCVD population. Per the AHA/ACC Guideline, VHR status was defined by ≥2 major ASCVD events or 1 major ASCVD event and ≥2 high-risk conditions. CART analysis was performed on training and validation datasets. A random forest model was used to verify results. RESULTS: Of 180,669 ASCVD patients identified, 58% were VHR. Among patients with a history of myocardial infarction (MI) or recent acute coronary syndrome (ACS), 99% and 96% were classified as VHR, respectively. Both CART and random forest models identified recent ACS, ischemic stroke, hypertension, peripheral artery disease, history of MI, and age as the most important predictors of VHR status. Using five rules identified by CART analysis, fewer than 50% of risk factors were required to assign VHR status. CONCLUSION: CART analysis helped to streamline the identification of VHR patients based on a limited number of rules and risk factors. This approach may help improve clinical decision making by simplifying ASCVD risk assessment at the point of care. Further validation is needed, however, in more diverse populations.

Outcomes of patients hospitalized for acute pulmonary embolism by obstructive sleep apnea status.

Pulmonary embolism (PE) is a major cause of cardiovascular morbidity and mortality. Obstructive sleep apnea (OSA) is increasingly recognized in the aging population, especially with the rising obesity epidemic. The impact of OSA on inpatient mortality in PE is not well understood. We used the Nationwide Inpatient Sample databases from 2005 to 2016 to identify 755,532 acute PE patients (age≥18 years). Among these, 61,050 (8.1%) were OSA+. Temporal trends in length of stay, inpatient mortality, and its association with OSA in PE patients were analyzed. The proportion of PE patients who were OSA+ increased from 2005 to 2016. OSA+ PE patients were younger and predominantly men. Despite a higher prevalence of traditional risk factors for inpatient mortality in OSA+ patients, OSA was associated with a lower risk of mortality in PE patients (odds ratio, 95% confidence interval; p: unadjusted 0.56, 0.53-0.58; p < 0.0001 and adjusted 0.55, 0.52-0.58; p < 0.0001). Overall mortality and length of stay in PE patients decreased over time. Relative to OSA- patients, there was a slight increase in mortality among OSA+ PE patients over time, although the length of stay remained unchanged between the two groups. In conclusion, OSA+ PE patients had a lower inpatient mortality compared to OSA- patients despite a higher prevalence of traditional mortality risk factors. Secondary pulmonary hypertension related to OSA with preconditioning of the right ventricle to elevated afterload may potentially explain the protective effect of OSA on mortality in PE. However, mechanistic studies need to further elucidate the links behind this association.

Utility of non-HDL-C and apoB targets in the context of new more aggressive lipid guidelines.

OBJECTIVE: Major guidelines recommend the use of secondary targets, such as non-HDL-C and apoB, to further reduce cardiovascular risk. We aimed to evaluate the proportion at which newer, more aggressive secondary lipid targets are exceeded in patients with LDL-C < 70 mg/dL estimated by Friedewald (LDLf-C) and Martin/Hopkins equations (LDLm-C). METHODS: We analyzed patients from the Very Large Database of Lipids with fasting lipids and estimated LDL-C <70 mg/dL by the Friedewald equation and Martin/Hopkins algorithm. Patients were categorized into three groups: LDL-C <40, 40-54 and 55-69 mg/dL. We calculated the proportion of patients with non-HDL-C and apoB above high-risk targets (non-HDL-C ≥ 100 and apoB ≥ 80mg/dL) for those with LDL-C 55-69 mg/dL and very high-risk targets (non-HDL-C ≥ 85 and apoB ≥ 65mg/dL) for those with LDL-C < 40 mg/dL and 40-54 mg/dL. RESULTS: In patients with LDLf-C < 40 mg/dL, ~8 and ~4% did not meet high-risk secondary targets and ~21 and 25% did not meet very high-risk secondary targets for non-HDL-C and apoB, respectively. However, in patients with LDLm-C < 40 mg/dL <1% did not meet high-risk targets, while only 3% did not meet the very-high risk secondary target for apoB and none exceeded the very-high risk secondary target for non-HDL-C. Among individuals with LDL-C< 40 mg/dL, there were increasing proportions of individuals not meeting the very high-risk secondary apoB target at greater triglyceride levels, reaching up to ~19% using LDLm-C compared to ~60% using LDLf-C when triglyceride levels were 200-399 mg/dL. There were higher proportions of individuals not meeting high and very-high risk targets as triglyceride levels increased among those with LDL-C 40-54 and 55-69 mg/dL. CONCLUSION: In a large, US cross-sectional sample of individuals with LDL-C < 70 mg/dL, secondary non-HDL-C and apoB targets overall provide modest utility. However, attainment of very high-risk cutpoints for non-HDL-C and apoB is not achieved in a significant fraction of patients with triglycerides 200-399 mg/dL, even when using a more accurate calculation of LDL-C.

Importance of the triglyceride level in identifying patients with a Type III Hyperlipoproteinemia phenotype using the ApoB algorithm.

BACKGROUND: Hyperlipoproteinemia Type III (HLP3), also known as dysbetalipoproteinemia, is defined by cholesterol and triglyceride (TG) enriched remnant lipoprotein particles (RLP). The gold standard for diagnosis requires demonstration of high remnant lipoprotein particle cholesterol (RLP-C) by serum ultracentrifugation (UC), which is not readily available in daily practice. The apoB algorithm can identify HLP3 using total cholesterol (TC), plasma triglyceride (TG), and apoB. However, the optimal TG cutoff is unknown. OBJECTIVE: We analyzed apoB algorithm defined HLP3 at different TG levels to optimize the TG cutoff for the algorithm. METHODS: 128,485 UC lipid profiles in the Very Large Database of Lipids (VLDbL) were analyzed. RLP-C was assessed at TG ≥ 133 mg/dL, ≥175 mg/dL, ≥200 mg/dL, and ≥ 250 mg/dL. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and prevalence adjusted and bias-adjusted kappa (PABAK) were calculated against UC Criterion (VLDL-C/TG ≥ 0.25) for HLP3. RESULTS: The median age (IQR) was 57 years (46-68). 45% were men, 20.1% had diabetes, and 25.5% had hypertension. The median RLP-C level for the TG cutoffs (mg/dL) of ≥ 133, ≥ 175, ≥ 200, and ≥ 250 were 34, 43, 50, and 62 mg/dL, respectively, compared to 67 mg/dL in UC defined HLP3. TG ≥ 133 mg/dL yielded optimal results (Sn 29.5%, Sp 98.5%, PABAK 0.96, PPV 13.6%, NPV 99.4%). CONCLUSION: TG ≥ 133 mg/dL allows for high sensitivity in screening for HLP3. Higher TG cutoffs may identify more severe HLP3 phenotypes, but with a large loss in sensitivity for HLP3.

Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels.

Importance: Low-density lipoprotein cholesterol (LDL-C) is typically estimated with the Friedewald or Martin/Hopkins equation; however, if triglyceride levels are 400 mg/dL or greater, laboratories reflexively perform direct LDL-C (dLDL-C) measurement. The use of direct chemical LDL-C assays and estimation of LDL-C via the National Institutes of Health Sampson equation are not well validated, and data on the accuracy of LDL-C estimation at higher triglyceride levels are limited. Objective: To compare an extended Martin/Hopkins equation for triglyceride values of 400 to 799 mg/dL with the Friedewald and Sampson equations. Design, Setting, and Participants: This cross-sectional study evaluated consecutive patients at clinical sites across the US with patient lipid distributions representative of the US population in the Very Large Database of Lipids from January 1, 2006, to December 31, 2015, with triglyceride levels of 400 to 799 mg/dL. Data analysis was performed from November 9, 2020, to March 23, 2021. Main Outcomes and Measures: Accuracy in LDL-C classification according to guideline-based categories and absolute errors between estimated LDL-C and dLDL-C levels. Patients were randomly assigned 2:1 to derivation and validation data sets. Levels of dLDL-C were measured by vertical spin-density gradient ultracentrifugation. The LDL-C levels were estimated using the Friedewald method, with a fixed ratio of triglycerides to very low-density lipoprotein cholesterol (VLDL-C ratio of 5:1), extended Martin/Hopkins equation with a flexible ratio, and Sampson equation with VLDL-C estimation by multiple least-squares regression. Results: A total of 111 939 patients (mean [SD] age, 52 [13] years; 65.0% male) with triglyceride levels of 400 to 799 mg/dL were included, representing 2.2% of 5 081 680 patients in the database. Across all individual guideline LDL-C classes (<40, 40-69, 70-99, 100-129, 130-159, 160-189, and ≥190), estimation of LDL-C by the extended Martin/Hopkins equation was most accurate (62.1%) compared with the Friedewald (19.3%) and Sampson (40.4%) equations. In classifying LDL-C levels less than 70 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (67.3%) compared with Friedewald (5.1%) and Sampson (26.4%) equations. In addition, for classifying LDL-C levels less than 40 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (57.2%) compared with the Friedewald (4.3%) and Sampson (14.4%) equations. However, considerable underclassification of LDL-C occurred. The magnitude of error between the Martin/Hopkins equation estimation and dLDL-C was also smaller: at LDL-C levels less than 40 mg/dL, 2.7% of patients had 30 mg/dL or greater differences between dLDL-C and estimated LDL-C using the Martin/Hopkins equation compared with the Friedewald (92.5%) and Sampson (38.7%) equations. Conclusions and Relevance: In this cross-sectional study, the extended Martin/Hopkins equation offered greater LDL-C accuracy compared with the Friedewald and Sampson equations in patients with triglyceride levels of 400 to 799 mg/dL. However, regardless of method used, caution is advised with LDL-C estimation in this triglyceride range.

Chronic inflammation in psoriasis promotes visceral adiposity associated with noncalcified coronary burden over time.

BACKGROUNDPsoriasis is a chronic inflammatory skin disease associated with increased obesity, noncalcified coronary artery burden (NCB), and incident myocardial infarction. Here, we sought to assess the relationship among inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis.METHODSConsecutive psoriasis patients underwent coronary CT angiography to quantify NCB and abdominal CT to calculate VAT at baseline (n = 237), 1 year (n = 176), and 4 years (n = 50).RESULTSPatients with high levels of high-sensitivity C-reactive protein (hs-CRP) had significantly greater visceral adiposity (17,952.9 ± 849.2 cc3 vs. 13370.7 ± 806.8 cc3, P < 0.001) and noncalcified coronary burden (1.26 ± 0.03 vs. 1.07 ± 0.02 mm2) than those with low levels of hs-CRP. Those with higher levels of VAT had more systemic inflammation (hs-CRP, median [IQR], 2.5 mg/L [1.0-5.3 mg/L] vs. 1.2 mg/L [0.6-2.9 mg/L]), with approximately 50% higher NCB (1.42 ± 0.6 mm2 vs. 0.91 ± 0.2 mm2, P < 0.001). VAT associated with NCB in fully adjusted models (ß = 0.47, P < 0.001). At 1-year follow-up, patients who had worsening hs-CRP had an increase in VAT (14,748.7 ± 878.1 cc3 to 15,158.7 ± 881.5 cc3; P = 0.03), whereas those who had improved hs-CRP improved their VAT (16,876.1 ± 915.2 cc3 to 16310.4 ± 889.6 cc3; P = 0.04). At 1 year, there was 10.3% reduction in NCB in those who had decreased VAT (ß = 0.26, P < 0.0001), which persisted in a subset of patients at 4 years (ß = 0.39, P = 0.003).CONCLUSIONSInflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its effect on early atherogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778569.FUNDINGThis study was supported by the National Heart, Lung, and Blood Institute Intramural Research Program (HL006193-05), the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (no. 2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and Elsevier as well as private donors.

Association Between Soluble Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 and Coronary Artery Disease in Psoriasis.

Importance: Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis. Objective: To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time. Design, Setting, and Participants: In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year. Exposures: Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay. Main Outcomes and Measures: Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status. Results: Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P < .001), and were associated with Psoriasis Area Severity Index (PASI) score (ß = 0.23; 95% CI, 0.082-0.374; P = .003). Moreover, sLOX-1 was associated with NCB independent of hyperlipidemia status (ß = 0.11; 95% CI, 0.016-0.200; P = .023), an association which persisted after adjusting for traditional cardiovascular risk factors, statin use, and biologic psoriasis treatment (ß = 0.10; 95% CI, 0.014-0.193; P = .03). At 1 year, in those who had clinical improvement in PASI (eg, >50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (ß = 0.14; 95% CI, 0.028-0.246; P = .02). Conclusions and Relevance: Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.

SGLT-2 Inhibitors and GLP-1 Agonists: First-Line Therapy for Diabetes With Established Cardiovascular Disease.

There is a growing body of evidence that diabetes represents a significant and largely modifiable risk factor for cardiovascular disease (CVD). It is known to markedly increase the risk of CVD-with CVD accounting for 2 of every 3 deaths in patients with diabetes. It is suggested that once patients with diabetes develop clinical coronary disease, they have a grim prognosis. In 2008, the Food and Drug Association mandated the evidence of CV safety in any new diabetic therapy, leading to a multitude of large CV outcome trials to assess CV risk from these medications. However, several of these outcome trials with novel antidiabetic therapies have demonstrated not only safety but a clear and definite CV advantage in patients with type 2 diabetes. In this review, we discuss 2 relatively newer classes of diabetic drugs, sodium glucose cotransport 2 inhibitors and glucagon-like peptide 1 agonists, evaluate their efficacy in improving CV outcomes, and discuss the future of CV prevention with these agents.

Sex-Based Differences in Left Ventricular Assist Device Utilization: Insights From the Nationwide Inpatient Sample 2004 to 2016.

BACKGROUND: Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs). During the early pulsatile-flow device era, women had higher post-LVAD mortality and increased complications. However, knowledge about these differences in the continuous-flow device era is limited. Therefore, we sought to explore temporal trends in LVAD utilization and post-LVAD mortality by sex. METHODS AND RESULTS: Patients with LVAD implantation from 2004 to 2016 were identified using the Nationwide Inpatient Sample. Trends in LVAD utilization and post-LVAD inpatient mortality were compared by sex and device era. Although LVADs are being increasingly utilized for patients with advanced systolic heart failure, women continue to represent a smaller proportion of LVAD recipients-25.8% in 2004 to 21.9% in 2016 (P for trend, 0.91). Women had increased inpatient mortality after LVAD implantation compared with men in the pulsatile-flow era (46.9% versus 31.1%, P<0.0001) but not in the continuous-flow era (13.3% versus 12.1%, P=0.27; P for interaction=0.0002). Inpatient mortality decreased for both sexes over time after LVAD, with a sharp fall in 2008 to 2009. Female sex was independently associated with increased post-LVAD inpatient mortality beyond adjustment for demographics and risk factors during the pulsatile-flow era (odds ratio, 2.13; 95% CI, 1.45-3.10; P<0.0001) but not during the continuous-flow era (1.18; 0.93-1.48; P=0.16). CONCLUSIONS: Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy. Prospective studies are needed to confirm these findings.