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Background: Cardiovascular disease is the major cause of mortality in the United States. Despite lifestyle modification and traditional risk factor control residual inflammatory risk remains an untreated concern. Colchicine is an oral, medication that has been used for gout, mediterranean fever and pericarditis for decades. In recent trials, colchicine has been shown to reduce major adverse cardiovascular events, however the mechanism of benefit remains unclear. The objective of the randomized, double-blind, placebo controlled EKSTROM trial is to evaluate the effects of colchicine 0.5mg/day on atherosclerotic plaque., Methods: Eighty-four participants will be enrolled after obtaining informed consent and followed for 12 months. Eligible patients will be randomly assigned to colchicine 0.5mg/day or placebo in a 1:1 fashion as add-on to their standard of care. All participants will undergo coronary computed tomography angiography (CCTA) at baseline and at 12 months., Results: As of November 2023, the study is 100% enrolled with an expected end of study by the second quarter of 2024. The primary endpoint is change in low attenuation plaque volume as measured by CCTA. Secondary endpoints include change in volume of different plaque types (including total atheroma volume, noncalcified plaque volume, dense calcified plaque volume, remodeling index), change in inflammatory markers (IL-6, IL-1β, IL-18, hs-CRP), change in pericoronary adipose tissue attenuation, change in epicardial adipose tissue volume and attenuation and change in brachial flow mediated dilation., Conclusion: EKSTROM is the first randomized study to assess the effects of colchicine on plaque progression, pericoronary and epicardial fat. EKSTROM will provide important information on the mechanistic effects of colchicine on the cardiovascular system., Trial Registration: Registry: clinicaltrials.gov, Registration Number: NCT06342609 url: https://www., Clinicaltrials: gov/study/NCT06342609?term=EKSTROM&rank=1., Competing Interests: Conflict of Interest All authors report no conflicts of interest related to the current submission., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Despite innovations in pharmacotherapy to lower lipoprotein cholesterol and apolipoprotein B, risk factors for atherosclerotic cardiovascular disease (ASCVD), ASCVD persists as the leading global cause of mortality. Elevations in low-density lipoprotein cholesterol (LDL-C) are a well-known risk factor and have been a main target in the treatment of ASCVD. The latest research suggests that ketogenic diets are effective at improving most non-LDL-C/apolipoprotein B cardiometabolic risk factors. However, ketogenic diets can induce large increases in LDL-C to >190 mg/dl in some individuals. Interestingly, these individuals are often otherwise lean and healthy. The influence of increased levels of LDL-C resulting from a carbohydrate-restricted ketogenic diet on the progression of atherosclerosis in otherwise metabolically healthy individuals is poorly understood. This observational study aims to assess and describe the progression of coronary atherosclerosis in this population within 12 months., Methods: Hundred relatively lean individuals who adopted ketogenic diets and subsequently exhibited hypercholesterolemia with LDL-C to >190 mg/dl, in association with otherwise good metabolic health markers, were enrolled and observed over a period of 12 months. Participants underwent serial coronary computed tomography angiography scans to assess the progression of coronary atherosclerosis in a year., Results: Data analysis shall begin following the conclusion of the trial with results to follow., Conclusion: Ketogenic diets have generated debate and raised concerns within the medical community, especially in the subset exhibiting immense elevations in LDL-C, who interestingly are lean and healthy. The relationship between elevated LDL-C and ASCVD progression in this population will provide better insight into the effects of diet-induced hypercholesterolemia., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Epicardial adipose tissue (EAT) may enhance the risk of coronary artery disease (CAD). We investigated the relationship between EAT density (a maker of local inflammation) and coronary plaque characteristics in stable CAD patients. This study included 123 individuals who underwent coronary artery calcium scan and coronary CT angiography to evaluate CAD. Plaque characteristics were analyzed by semi-automated software (QAngio, Leiden, Netherlands). Non-contrast CT scans were used to measure EAT density (HU) and volume (cc) (Philips, Cleveland, OH). Multivariate regression models were used to evaluate the association of EAT density and volume with different plaque types. The mean (SD) age was 59.4±10.1 years, 53% were male, the mean (SD) EAT density was -77.2±4.6 HU and the volume was 118.5±41.2 cc. After adjustment for cardiovascular risk factors, EAT density was associated with fibrous fatty (FF) plaque (p<0.03). A 1 unit increase in HU was associated with a 7% higher FF plaque, and lower EAT density is independently associated to FF plaque. The association between EAT density and fibrous (p=0.08), and total noncalcified (p=0.09) plaque trended toward but did not reach significance. There was no association between EAT volume and any plaque type. These results suggest that inflammatory EAT may promote coronary atherosclerosis. Therefore, non-contrast cardiac CT evaluation of EAT quality can help better assess cardiovascular risk., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Colchicine is an anti-inflammatory medication, classically used to treat a wide spectrum of autoimmune diseases. More recently, colchicine has proven itself a key pharmacotherapy in cardiovascular disease (CVD) management, atherosclerotic plaque modification, and coronary artery disease (CAD) treatment. Colchicine acts on many anti-inflammatory pathways, which translates to cardiovascular event reduction, plaque transformation, and plaque reduction. With the FDA's 2023 approval of colchicine for reducing cardiovascular events, a novel clinical pathway opens. This advancement paves the route for CVD management that synergistically merges lipid lowering approaches with inflammation inhibition modalities. This pioneering moment spurs the need for this manuscript's comprehensive review. Hence, this paper synthesizes and surveys colchicine's new role as an atherosclerotic plaque modifier, to provide a framework for physicians in the clinical setting. We aim to improve understanding (and thereby application) of colchicine alongside existing mechanisms for CVD event reduction. This paper examines colchicine's anti-inflammatory mechanism, and reviews large cohort studies that evidence colchicine's blossoming role within CAD management. This paper also outlines imaging modalities for atherosclerotic analysis, reviews colchicine's mechanistic effect upon plaque transformation itself, and synthesizes trials which assess colchicine's nuanced effect upon atherosclerotic transformation., Competing Interests: Declaration of competing interest Matthew J. Budoff discloses the following: received grants from the following companies: Novo Nordisk, Novartis, Astrazeneca, Heartflow, GE Healthcare, Amgen, and Boehringer Ingleheim, Department of Defense, Centers for Disease Control and the National Institutes of Health. Dr. Budoff received honoraria from Novo Nordisk, Esperion, Astrazeneca, Merck, Janssen, and Eli Lilly. Jonathon Leipsic is a consultant to and holds stock options in HeartFlow and Circle CVI and modest speaking fees from Philips and GE Healthcare. All the rest of authors have no conflicts to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Miscarriage is a major public health concern in low and middle-income countries (LMICs) like Nepal. This study aims to examine the factors associated with miscarriage among pregnant women of reproductive age (15-49 years) in the past 15 years., Methods: There were a total of weighted sample of 26,376 cross-sectional pregnancy data from Nepal Demographic and Health Surveys (NDHS) 2001, 2006, 2011, and 2016 combined together, which was used in the study. Multilevel logistic regression analysis that adjusted for cluster and survey weights was used to identify factors associated with miscarriage among pregnant women of reproductive age in Nepal., Results: The results showed that maternal age, contraception, tobacco smoking, wealth index, respondents' educational status, and, caste/ethnicity were found to be strong factors of miscarriage in Nepal. The likelihood of having a miscarriage among older women (≥40 years) was more than 100% (aOR = 2.12, 95% CI [1.73, 2.59]), among non-users of contraception was 88.9% (aOR = 1.88, 95% CI [1.68, 2.11]) (p<005) and non-smoking women had a 19% lower odds of miscarriage (aOR = 0.81, 95% CI [0.69, 0.95]). Respondents from the richest wealth index had 50% (aOR = 1.50, 95% CI [1.22, 1.85]) higher likelihood of miscarriage. Mothers with only primary education had a 25% higher chance of miscarriage (aOR = 1.25, 95% CI [1.09, 1.44]) compared to those with secondary and higher secondary education. In relation to caste/ethnicity, Dalits had 13% lesser likelihood (aOR = 0.87, 95% CI [0.74, 1.02]) and Janajatis had 26% lower chances of a miscarriage than Brahmin/Chettri (aOR = 0.74, 95% CI [0.64, 0.85])., Conclusion: Findings from this study show that miscarriages are associated with maternal age, use of contraception, smoking, wealth index, caste, and ethnicity. Interventions aimed to improve use of contraceptives, avoiding smoking and pregnancy planning on the basis of maternal age, are needed to prevent miscarriage. Also, women from Brahmin ethinicity and those with the highest income index require greater attention when it comes to miscarriage prevention strategies in Nepal., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hamal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Among the several anthropogenic factors, power lines are increasingly regarded as one of the most significant hazards to bird species, primarily owing to collisions and electrocutions. Nepal has comparatively fewer studies on the impact of power line collisions and electrocution on birds compared with developed nations. From November 2021 to May 2022, we assessed the effect of power line collisions and electrocutions on the mortality of birds in the Putalibazar Municipality of the Syangja district of Nepal. We established 117 circular plots in diverse habitats, including agricultural lands, forests, settlements, and river basins, along a 30.6 km long distribution line. Within 18 plots, we detected 43 fatalities of 11 species (17 individuals of six species due to collision and 26 individuals of eight species due to electrocution). House Swift ( Apus nipalensis ) and Common Myna ( Acridotheres tristis ) were the primary victims of the collision, whereas House Crow ( Corvus splendens ) and Rock Pigeon ( Columba livia ) were frequently observed electrocuted. We also recorded the electrocution of the critically endangered White-rumped Vulture ( Gyps bengalensis ). The total rate of bird power line collisions per kilometer was 0.55 birds, while the total electrocution rate per 10 poles was 2.22. The bird abundance, distance to agricultural regions, and proximity to human settlements were found to have a strong relationship with the mortality of birds caused by power lines. In order to reduce power line collisions and electrocution fatalities, we recommend conducting a detailed bird population study prior to determining the route of distribution lines., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Purpose: To test the benefits of Solumedrol treatment in sepsis patients with a blunted adrenocorticotropic hormone (ACTH)-cortisol response (delta <13 µg/dL) with regard to the number of days on ventilator, days on intravenous blood pressure support, length of time in an intensive care unit (ICU), 14-day mortality, and 28-day mortality. The trial was prospective, randomized, and double-blind. As part of a larger sepsis trial, 54 patients with sepsis had an intravenous ACTH stimulation test using 250 µg of ACTH, and serum cortisol was measured at times 0, 30, and 60 min. Eleven patients failed to increase their cortisol concentration above 19.9 µg/dL and were excluded from the clinical trial as they were considered to have adrenal insufficiency. The remaining 43 patients had a baseline cortisol of 32 ± 1 µg/dL increased to 38 ± 3 µg/dL at 30 min and 40 ± 3 at 60 min. All cortisol responses were <12.9 µg/dL between time 0 and time 60, which is defined as a blunted cortisol response to intravenous ACTH administration. Twenty-one were randomized to receive 20 mg of intravenous Solumedrol and 22 were randomized to receive a matching placebo every 8 h for 7-days. There was no significant difference between the two randomized groups. Data analysis was carried out bya two-tailed test and P  < .05 as significant., Results: The mean age was 51 ± 2 (mean ± SEM) with 61% female. Groups were well matched with regard to APACHE III score in Solumedrol versus placebo (59 ± 6 vs 59 ± 6), white blood cell count (18.8 ± 2.2 vs 18.6 ± 2.6), and incidence of bacteremia (29 vs 39%). The 28-day mortality rate was reduced in the Solumedrol treated arm (43 ± 11 vs 73 ± 10%; P  < .05). There was no change in days in ICU, days on blood pressure agents, or days on ventilator. Seven days of high-dose intravenous Solumedrol treatment (20 mg every 8 h) in patients with a blunted cortisol response to ACTH was associated with an improved 28-day survival. This small study suggests that an inability to increase endogenous cortisol production in patients with sepsis who are then provided steroid treatment could improve survival.

Aim: To assess the effects of health locus of control-based education programme (HLCEP) on self-management, health locus of control and glycated haemoglobin (HbA1c) among type 2 diabetes mellitus (T2DM)., Design: Quasi-experimental study., Methods: The study recruited 120 T2DM participants from May-September 2020. The control group received one-week in-hospital care and 12-week follow-up. The intervention group received additional HLCEP. The self-management and the health locus of control were measured by using the Summary of Diabetes Self-care Activities and the Multidimensional Health Locus of Control at baseline and the 4th and 12th week after discharge. The HbA1c was collected at baseline and the 12th week after discharge. The generalized estimating equation analysis was performed to assess the intervention effects., Results: The intervention group has statistically significantly higher scores on the overall level of self-management, dietary management, foot care, medication management and internal health locus of control, while a lower HbA1c level than the control group., (© 2021 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Background: Coronary artery disease (CAD) genomic risk scores (GRS), as FDR202, GRS46K, 1.7M, and MetaGRS, help in assessing cardiovascular related morbidity and mortality. Interventions to adhere to a healthy lifestyle as a means of prevention based on the GRS have a potential to greatly reduce incident CAD event rates. We performed a prospective observational study to see the relationship between GRS and coronary artery calcium (CAC) scoring in individuals who are at risk., Methods: 104 subjects with mean age 55.1 ± 8.8 years were enrolled and consented and all the participants underwent CAC scoring. 55 (53%) were male. CAC score was measured using the Agatston method. Spearman correlation analysis assessed relationships between GRS scores and CAC scores, in the entire sample and in subjects with CAC score greater than zero. Multivariable linear regression analyzed associations while adjusting potential confounding variables., Results: Mean ± SD CAC score of the study population was 49.0 ± 130. A significant negative correlation was noted between FDR202 Prevalence and total CAC Score in 39 subjects with CAC >0, r = -0.35, p = 0.02. Multivariable analysis shows a significant association between FDR202 prevalence and log adjusted CAC score in subjects with CAC >0 while adjusting age, gender, hypertension and hyperlipidemia (β = -0.2, SE = 0.1, p = 0.04). No significant correlations were found between GRS46K, 1.7M, and MetaGRS with CAC score., Conclusion: Additional research is necessary in a larger population to evaluate the potential role of GRS for the detection of CAD. This allows the individuals to adopt a healthy lifestyle modification to minimize the cardiovascular risk and delays the onset of most diseases of old age to prolong the life., Competing Interests: Declaration of competing interest Matthew J. Budoff, M.D., FACC discloses work for the National Institutes of Health and General Electric Healthcare; All other authors have no conflicts of interest. Study was funded by trineOMICS, Malibu, CA., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Introduction: Hypothyroidism is highly prevalent in end-stage kidney disease patients, and emerging data show that lower circulating thyroid hormone levels lead to downregulation of vascular calcification inhibitors and coronary artery calcification (CAC) in this population. To date, no studies have examined the association of serum thyrotropin (TSH), the most sensitive and specific single biochemical metric of thyroid function, with CAC risk in hemodialysis patients., Methods: In secondary analyses of patients from the Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients trial, we examined serum TSH levels and CAC risk assessed by cardiac computed tomography scans collected within a 90-day period. We evaluated the relationship between serum TSH with CAC Volume (VS) and Agatston score (AS) (defined as >100 mm3 and >100 Houndsfield Units, respectively) using multivariable logistic regression., Results: Among 104 patients who met eligibility criteria, higher TSH levels in the highest tertile were associated with moderately elevated CAC VS and AS in case-mix-adjusted analyses (ref: lowest tertile): adjusted ORs (95% CIs) 4.26 (1.18, 15.40) and 5.53 (1.44, 21.30), respectively. TSH levels >3.0 mIU/L (ref: ≤3.0 mIU/L) were also associated with moderately elevated CAC VS and AS. In secondary analyses, point estimates of incrementally lower direct free thyroxine levels trended toward elevated CAC VS and AS, although associations did not achieve statistical significance., Conclusions: In hemodialysis patients, higher serum TSH was associated with elevated CAC VS and AS. Further studies are needed to determine if thyroid hormone supplementation can attenuate CAC burden in this population., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Thyroid dysfunction is a highly prevalent yet under-recognized complication in hemodialysis patients. In the general population, hypothyroidism has been associated with endothelial dysfunction due to impaired vasodilator synthesis and activity. Little is known about the association of serum thyrotropin (TSH), the most sensitive and specific single biochemical metric of thyroid function, with endothelial function in hemodialysis patients., Methods: In a secondary analysis of 99 patients from the Anti-inflammatory and anti-oxidative nutrition in hypoalbuminemic dialysis patients (AIONID) trial, we examined measurements of serum TSH and endothelial function ascertained by fingertip digital thermal monitoring (DTM), a novel method used to measure micro-vascular reactivity, collected within a 90-day period. DTM was used to measure changes in fingertip temperature during and after an ischemic stimulus (blood pressure cuff occlusion) as an indicator of changes in blood flow, and two DTM indices were assessed, namely adjusted (a) Temperature Rebound (TR), defined as the maximum temperature rebound post-cuff deflation, and adjusted (b) Area Under the Temperature Curve (TMP-AUC), defined as area under the curve between the maximum and minimum temperatures. We examined the relationship between serum TSH with impaired TR (separately) and TMP-AUC (both defined as less than the median level of observed values) using multivariable logistic regression., Findings: In unadjusted and case-mix analyses, higher serum TSH levels (defined as the three highest quartiles) were associated with lower (worse) TR (ref: lowest TSH quartile): ORs (95% CI) 2.64 (1.01-6.88) and 2.85 (1.08-7.57), respectively. In unadjusted and case-mix analyses, higher TSH levels were associated with lower (worse) TMP-AUC: ORs (95% CI) 2.64 (1.01-6.88) and 2.79 (1.06-7.38), respectively., Discussion: In HD patients, higher serum TSH levels were associated with worse micro-vascular reactivity measured by DTM. Further studies are needed to determine if thyroid hormone supplementation improves endothelial function in hemodialysis patients with lower levels of thyroid function., (© 2021 International Society for Hemodialysis.)

Chediak-Higashi syndrome is a rare immunodeficiency disorder for which hematopoietic stem cell transplant (HSCT) is the only curative treatment option. HSCT only corrects the hematologic and immunologic manifestations of the disease but neurologic complications may still progress after transplant. Haploidentical HSCT (haplo-HSCT) has evolved as a feasible alternative for patients with primary immunodeficiency. More recently, there has been use of haplo-HSCT with post-transplant cyclophosphamide. However, only 4 cases of Chediak-Higashi syndrome have been reported using this approach. Here, the authors describe a case of a 17-month-old boy who was successfully treated by haplo-HSCT with reduced-toxicity conditioning (fludarabine/treosulfan/melphalan) and post-transplant cyclophosphamide., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

We intended to assess the ability of current-generation 256-slice coronary CT angiography (CCTA) to measure left atrial volume (LAV), comparing patients with a high heart rate (HiHR) of at least 70 bpm and patients with heart rate variability such as atrial fibrillation (AFib). Methods: Using the prospective Converge Registry of patients undergoing 256-detector CCTA on a Revolution scanner, we enrolled 121 HiHR patients (74 men; mean age, 62.7 ± 12.5 y) and 102 AFib patients (72 men; mean age, 60.5 ± 11.0 y) after obtaining informed consent. Quantitative data analysis of LAV was performed using automated methods, and end-systolic phases were chosen for measurements from CCTA. A Student t test, Wilcoxon rank-sum test, or χ 2 test assessed baseline parameters. Univariate and multivariate linear regression analysis was used to assess LAV and LAV index (LAVI) while adjusting potentially confounding variables. Results: Mean LAV was significantly higher in AFib subjects (148.6 ± 57.2 mL) than in HiHR subjects (102.1 ± 36.5 mL) ( P < 0.0001). Similarly, mean LAVI was significantly higher in AFib subjects (72.4 ± 28.1 mL/m 2 ) than in HiHR subjects (51.5 ± 19.0 mL/m 2 ) ( P < 0.0001). After adjusting for age, body mass index, sex, diabetes, hypertension, hyperlipidemia, and smoking, subjects with AFib had, on average, LAV measures higher by 41.2 ± 6.7 mL and LAVI values higher by 23.1 ± 3.4 mL/m 2 ( P < 0.0001). Conclusion : Misalignment and motion artifacts in CCTA images affect diagnostic CT performance, especially in patients with elevated heart rates or profound arrhythmia. However, the new-generation Revolution CCTA provides detailed information on left-atrium-complex morphology and function, in addition to coronary anatomy, in HiHR and AFib patients without additional radiation, scanning, or contrast requirements., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Sepsis is a global health burden that needs intensive medical care. Thrombocytopenia in sepsis is well known to increase morbidity as well as mortality. Several studies have been performed both in animal models and in humans to understand the mechanism by which sepsis causes thrombocytopenia. Recent studies have shown that inhibiting thrombocytopenia improves outcomes in sepsis patients. Understanding these mechanisms to identify targets in use of newer treatment modalities besides using resuscitation measures, antibiotics and removal of thrombocytopenia inducing agent could potentially help us improve outcomes in sepsis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Coronary artery disease (CAD) is leading cause of morbidity and mortality among type 2 diabetics (T2DM)., Methods: 140 T2DM will be enrolled in randomized, double blind, placebo controlled Semaglutide Treatment On Coronary Plaque Progression (STOP) trial to determine effect of weekly subcutaneous semaglutide on coronary plaque progression. All participants will undergo Coronary Artery Calcium (CAC) Scoring and Coronary Computed Tomography Angiography (CCTA) at our center. A Fisher test, ANOVA and Kruskal Wallis were used., Results: As of May 2020, 87 patients (81%) randomized (mean age 56.4 ± 8.4 yrs. and 62% male) with documented CAD by CCTA. Approximately 20% of screened study population were screen failed due to normal coronaries (n= 14) or HbA1C<7 (n=7). Of interest, 14 persons with diabetes with normal coronaries (no calcification) were significantly more likely to be females (21% vs 62%), have higher glomerular filtration rate (106.5 ± 19.4 vs 89.9 ± 22.6 mL/min/1.73m 2 ; p= 0.006), and younger (53.4 ± 9.0 vs 56.4 ± 8.4 yrs.; p=0.02) than those who were randomized., Conclusion: Among T2DM, there is a significant portion who have normal coronary arteries and may have a better prognosis. Excluding these participants from cardiovascular studies may improve power and decrease sample size., Competing Interests: Declaration of competing interest Matthew J. Budoff, M.D., FACC discloses work for the National Institutes of Health and General Electric Healthcare; All other authors have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Evidence suggests that asymptomatic and mild SARS-CoV-2 infections comprise > 95% of all cases. Developing a test that indicates past infection and possible immunity against the virus is important. We administered 244 antibody tests to three groups of high-risk population. The test consisted of an IgG component and an IgM component. The overall IgM/IgG positivity for patients with none, mild, moderate, and severe symptoms were 21.1%, 21.8%, 14.2%, and 26.9%, respectively. Those with moderate or severe symptoms were no more or less likely to have positive antibody tests than those with no or mild symptoms.

CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis, diabetes and some cancers. Postulating that fusing a pyridine ring bearing hydrophobic substituents into the macrocyclic scaffold of CADA compounds may lead to potent compounds with improved properties, 17 macrocycles were synthesized, 14 with 12-membered rings having an isobutylene head group, two arenesulfonyl side arms, and fused pyridine rings bearing a para substituent. The analogs display a wide range of CD4 down-modulating and anti-HIV potencies, including some with greater potency than CADA, proving that a highly basic nitrogen atom in the 12-membered ring is not required for potency and that hydrophobic substituents enhance potency of pyridine-fused CADA compounds. Cytotoxicities of the new compounds compared favorably with those of CADA, showing that incorporation of a pyridine ring into the macrocyclic scaffold can produce selective compounds for potently down-modulating proteins of medicinal interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This study assessed efficacy of plant based bioequivalent nitrate complex, consist of vitamins, natural antioxidants and phytophenol rich food extracts to elevate nitric oxide (NO) bioavailability as determined by saliva conversion of nitrate (NO 3 - ) to nitrite (NO 2 - ) a required step to produce NO, in relationship to lowering blood pressure (BP) in both men and women., Methods: 67 individuals (26 men; mean age of 59.3 ± 9.0 yrs) with mean baseline systolic and diastolic BP >120 and 80 mmHg respectively were randomized to receive daily dosing of 314 mM NO 3 - or NO 3 - free (placebo) tablets in double-blinded study for 12 weeks (wks). Inorganic NO 3 - tablets consist of NO 3 - rich beetroot extract, thiamine nitrate, and potassium nitrate in the presence of ascorbic acid, to facilitate NO bioavailability., Results: The primary endpoint of the study was reduction in BP at 12 wks by improving endothelial function. At study conclusion, mean ± SD reduction in systolic BP (SBP) in the inorganic NO 3 - group was 12.5 ± 13.3 mmHg (p = 0.0007), as compared to 6.19 ± 11.39 mmHg (p = 0.004) in the placebo group, for a placebo-corrected reduction of -6.31 mmHg (95% CI 10.89-2.31, p = 0.04). NO 3 - also reduced diastolic BP by 4.7 ± 10.3 mmHg (p = 0.01), while no significant reduction in placebo group (1.98 ± 9.38 mmHg, p = 0.24) was noted. Endothelial function improved at 12 weeks by 0.8 ± 3.1 (p = 0.03) in active group when compared to 0.1 ± 1.8 (p = 0.82) in placebo group., Conclusion: Endothelial function improved robustly reducing both systolic and diastolic BP in hypertensive individuals with daily supplementation of dietary NO 3 - . CLINICALTRIALS., Gov Id: NCT03909789., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Cardio-ankle vascular index (CAVI) is an inexpensive, noninvasive, office-based method to evaluate arterial stiffness in the aorta and legs, which reflects the degree of coronary atherosclerosis. It has been applied clinically to assess arterial stiffness in patients who were diagnosed with coronary artery disease (CAD), stroke and those at risk. We intend to evaluate relationship between the CAVI and obstructive CAD., Methods: We enrolled 285 individuals with mean age of 55.8 ± 13.5 years, clinically referred for Coronary Artery Calcium (CAC) scoring and coronary computed tomography angiography (CCTA) at our site. After informed consent, CAVI measurements were done using a vascular screening system, VaSera VS-1500 AU (FUKUDA Denshi) on the same day of CCTA. CAC was measured using the Agatston method. A semiquantitative scale was used by CCTA readers to grade the extent of luminal stenosis as a percentage of the vessel diameter using visual estimations. We evaluated if CAVI was associated with severe stenosis (>50%) or CAC >100, defined as obstructive CAD., Results: The degree of CAC and severe coronary stenosis demonstrated significant correlation with CAVI (r = 0.44, P ≤ 0.0001 and r = 0.43, P ≤ 0.0001). Receiver operating characteristic curve analysis indicated that CAVI measure of 7.8 was an optimal cut-point for sensitivity and specificity in detecting obstructive CAD. Unadjusted logistic regression demonstrated CAVI >7.8, significantly associated with obstructive CAD [odds ratio (OR) = 4.60, 95% confidence interval (CI) (2.0-10.56), P = 0.0003] and CAC score >100 [OR = 6.96, 95% CI (3.68-13.17), P < 0.0001]., Conclusion: CAVI reflects coronary atherosclerosis and may be used as a screening tool for early identification of subclinical atherosclerosis in preventive care and optimize management.

Background and Aims: Dyslipidemia with elevated triglycerides (TGL) and low high-density lipoprotein cholesterol (HDL-C) predicts residual cardiovascular risk, despite goal LDL-C levels and optimal statin therapy. Coronary plaque characterization by CCTA can provide mechanistic understanding of coronary artery disease and associated prognosis. The role of HDL-C in the pathogenesis of atherosclerosis is not well understood in statin-treated patients with elevated TGL. We sought to examine the association of HDL-C levels with baseline coronary plaque volumes, namely total plaque (TP) and total non-calcified plaque (TNCP) volumes by CCTA in participants enrolled in the EVAPORATE trial., Methods: We analyzed 80 participants who were enrolled in the trial. Linear regression analysis as a univariate and multivariate model adjusted for significant cardiovascular risk factors was performed to evaluate independent association of HDL-C and baseline coronary plaque volumes. In an exploratory analysis, stratified by sex, we compared the association of serum HDL-C levels with baseline coronary plaque volumes in males and females., Results: Mean (SD) age of participants (n = 80) was 57.1 (8.6) years and 43% were male. Median (Inter Quartile Range/IQR) log-TNCP volume was 83.0 (0.1-7.3) mm 3 and median (IQR) log-TP volume was 144.8 (0.1-7.1) mm 3 . After adjustment for relevant clinical covariates including age, gender, BMI, hypertension, diabetes, past smoking and baseline TGL levels, increasing levels of HDL-C remain independently associated with lower baseline log-TNCP volumes (β: 0.043 ± 0.021, p = 0.042) and baseline log-TP volumes (β: 0.046 ± 0.022, p = 0.035) on CCTA. On stratifying by sex in a multivariable regression analysis, HDL-C levels were inversely associated with baseline log-TNCP volumes (β: 0.066 ± 0.026, p = 0.018) and log-TP volumes (β: 0.077 ± 0.025, p = 0.004) in females, but not in males (log-TNCP volumes β: 0.038 ± 0.034, p = 0.282) and log-TP volumes (β: -0.033 ± 0.036, p = 0.364)., Conclusions: In a cohort of statin treated patients with known atherosclerosis and residually elevated TGL, there was a significant inverse relationship between HDL-C levels and baseline coronary plaque, TP and TNCP volumes on CCTA. Our findings provide more detailed mechanistic evidence regarding the protective role of HDL-C in coronary atherosclerosis in a high-risk cohort. Further investigation to evaluate the interaction of HDL-C levels and coronary plaque volumes on differential CVD risk in statin-treated patients with elevated TGL levels is warranted., Competing Interests: Declaration of competing interest Dr Budoff has received grant support and is on the speaker's bureau for Amarin Pharmaceuticals. Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr. John R. Nelson discloses the following relationships: Advisory Board: Amarin; Speaker Bureau: Amarin, Boehringer Ingelheim, Amgen, Bostonheart Diagnostics; Stock: Pfizer, Amgen. The remaining authors report no disclosures., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Recent results from the Cardiovascular Trial of the Testosterone Trials showed that testosterone treatment of older men with low testosterone was associated with greater progression of noncalcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the Testosterone Trial., Methods: The Cardiovascular part of the trial included 170 men aged 65 years or older with low testosterone. Participants received testosterone gel or placebo gel for 12 months. The primary outcome was change in NCP volume from baseline to 12 months, as determined by coronary computed tomography angiography (CCTA). We assayed several markers of cardiovascular risk and analyzed each marker individually in a model as predictive variables and change in NCP as the dependent variable., Results: Of 170 enrollees, 138 (73 testosterone, 65 placebo) completed the study and were available for the primary analysis. Of 10 markers evaluated, none showed a significant association with the change in NCP volume, but a significant interaction between treatment assignment and waist-hip ratio (WHR) (P = 0.0014) indicated that this variable impacted the testosterone effect on NCP volume. The statistical model indicated that for every 0.1 change in the WHR, the testosterone-induced 12-month change in NCP volume increased by 26.96 mm3 (95% confidence interval, 7.72-46.20)., Conclusion: Among older men with low testosterone treated for 1 year, greater WHR was associated with greater NCP progression, as measured by CCTA. Other biomarkers and anthropometric measures did not show statistically significant association with plaque progression., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Endothelial dysfunction and atherosclerosis are linked by multiple mechanisms. Brachial artery flow-mediated dilation (FMD) rate is used to evaluate endothelial function and has been independently associated with adverse cardiac outcomes. The relationship between brachial artery FMD rate and severity of subclinical atherosclerosis by coronary computed tomography angiography (CCTA) is not understood. We hypothesized that brachial FMD is inversely associated with burden of subclinical atherosclerosis measured by CCTA., Methods: This is a retrospective study of 100 participants with intermediate cardiac risk and atypical symptoms to examine association between brachial artery FMD rate and surrogate markers of severity of subclinical atherosclerosis on CCTA. Multivariate linear regression analysis was used to understand the relationship between brachial artery FMD rate and markers of plaque burden on CCTA including coronary artery calcium (CAC) score, segment involvement score (SIS; total number of segments with any plaque), segment stenosis score (SSS, sum of maximal stenosis score per segment), and total plaque score (TPS, the sum of all segments plaque burden)., Results: 52 participants (42%) were female. Mean age of the cohort was 59.3 ± 10.4 years. After adjusting for traditional risk factors, brachial artery FMD rate was inversely associated with higher CAC, TPS, SIS and SSS (p < 0.05 for all). FMD <4.5 predicted the presence of CAC >0 and ≤ 100 most effectively, with a sensitivity of 62.2% and a specificity of 66.7%, respectively (area under the curve (AUC) of 0.5729, p = 0.0302). FMD <2.7 predicted the presence of CAC >100 most effectively, with a sensitivity of 34% and a specificity of 83% respectively (AUC of 0.6226, p = 0.0095)., Conclusions: Brachial FMD is independently associated with the presence and extent of subclinical atherosclerosis on CCTA. Our findings provide more detailed evidence that mechanistically, FMD, a surrogate marker of systemic endothelial dysfunction is a correlate of atherosclerotic burden, assessed by CCTA and CAC., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)