Publications by authors named "Nehal N Mehta"

228 Publications

Abdominal subcutaneous adipose tissue negatively associates with subclinical coronary artery disease in men with psoriasis.

Am J Prev Cardiol 2021 Dec 22;8:100231. Epub 2021 Aug 22.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Objective: Understand the relationship between abdominal subcutaneous adipose tissue (ASAT) and coronary atherosclerosis defined as noncalcified and lipid-rich necrotic core burden in psoriasis.

Methods: We performed a cross-sectional study of 232 participants (92 women) with psoriasis and without known cardiovascular disease. Participants underwent coronary computed tomography angiography to characterize coronary atherosclerosis burden and low dose abdominal computed tomography to quantify subcutaneous and visceral adipose tissue. Fat depot volumes were first adjusted for each participant's BMI (ASAT).

Results: In women, there was a positive correlation between ASAT and systemic inflammation as assessed by hs-C-reactive protein (r=0.30; p=.004) and GlycA (r=0.29; p=.007) as well as total cholesterol (r=0.24; p=.02) and low-density lipoprotein cholesterol (r=0.22; p=.04). In men, ASAT correlated with hs-C-reactive protein (r=0.18; p=.04) and insulin resistance (r=0.17; p=.04). In models fully adjusted for traditional cardiovascular risk factors, ASAT negatively associated with noncalcified and lipid-rich necrotic core burden in men (β= -0.17; p=.03, β= -0.20; p=.03, respectively), but not women (β= -0.06; p=.57, β= 0.09; p=.49, respectively) with psoriasis.

Conclusions: For a given BMI, ASAT negatively associated with coronary atherosclerosis burden in male participants with psoriasis. The observed sex-specific effects warrant further study of ASAT in states of chronic inflammation.
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http://dx.doi.org/10.1016/j.ajpc.2021.100231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441148PMC
December 2021

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents.

J Allergy Clin Immunol 2021 Jul 31. Epub 2021 Jul 31.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Mich. Electronic address:

Background: A major issue with the current management of psoriasis is our inability to predict treatment response.

Objective: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis.

Methods: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples.

Results: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders.

Conclusions: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.
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http://dx.doi.org/10.1016/j.jaci.2021.07.024DOI Listing
July 2021

GlycA measured by NMR spectroscopy is associated with disease activity and cardiovascular disease risk in chronic inflammatory diseases.

Am J Prev Cardiol 2020 Dec 7;4:100120. Epub 2020 Nov 7.

Division of Rheumatology and Immunology, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, 27701, USA.

GlycA is a biomarker of systemic inflammation, quantifying both the protein concentrations and glycosylation states of several acute phase proteins. GlycA has been shown to be associated with both subclinical atherosclerosis and with cardiovascular disease (CVD). GlycA levels are higher in acute and chronic inflammation. During ongoing systemic inflammatory processes, GlycA specific acute phase reactants and proteins undergo circulating concentration and glycosylation pattern changes, and these alterations are reflected in the GlycA NMR signal. Additionally, levels associate with ongoing disease severity in individuals with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis thus capturing active inflammation. Furthermore, in these disease states, GlycA is associated with cardiovascular disease (CVD) independent of traditional risk factors including C-reactive protein (CRP). Finally, GlycA levels decrease with exercise, weight loss, and systemic anti-inflammatory agents. Therefore, GlycA appears to be a promising new composite biomarker of active systemic inflammation including assessing CVD risk in patients with inflammatory diseases.
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http://dx.doi.org/10.1016/j.ajpc.2020.100120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315361PMC
December 2020

Psoriasis and Cardiometabolic Diseases: The Impact of Inflammation on Vascular Health.

Psoriasis (Auckl) 2021 21;11:99-108. Epub 2021 Jul 21.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Psoriasis is a common chronic inflammatory condition associated with a higher risk of cardiovascular disease. Psoriasis confers a dose-dependent increase in risk for the metabolic syndrome and its components. The metabolic syndrome and its components have been associated with higher coronary atherosclerosis in psoriasis and cardiovascular events in the general population. In this review, we discuss the role of inflammation and psoriasis in cardiometabolic diseases with a focus on the metabolic syndrome and its components. We highlight the relationship between psoriasis and important cardiovascular risk factors encompassed by obesity, dyslipidemia, insulin resistance and hypertension. Furthermore, we briefly highlight literature on anti-inflammatory therapies and their impact on the components of the metabolic syndrome as well as directly quantified coronary atherosclerosis burden.
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http://dx.doi.org/10.2147/PTT.S320016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312325PMC
July 2021

Subclinical Liver Disease is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.

J Invest Dermatol 2021 Jul 19. Epub 2021 Jul 19.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n=76 psoriasis participants and 76 controls), non-alcoholic fatty liver disease (NAFLD), assessed by the sonographic hepatorenal index (SHRI), was more prevalent in psoriasis than controls (61% vs 45%; p=.04). Psoriasis participants with NAFLD had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than psoriasis without NAFLD (61% vs 23%; p=.006) and controls with NAFLD (61% vs 32%; p<.05). SHRI was a determinant of subclinical atherosclerosis in psoriasis (OR, 3.5; p=.01). In the United States cohort, (n=162 psoriasis participants who underwent positron emission tomography and coronary CT angiography), those with high hepatic F-FDG uptake had higher noncalcified (1.3 (0.49 mm) vs 1.0 (0.40 mm)), fibrofatty (0.23 (0.15 mm) vs 0.11 (0.087 mm)), and lipid rich necrotic core (4.3 (2.3 mm) vs 3.0 (1.7 mm)) coronary burden (all p<.001,). Hepatic F-FDG uptake associated with noncalcified (β=0.28; p<.001), fibrofatty (β=0.49; p<.001) and lipid rich necrotic core (β=0.28; p=.003) burden. These results demonstrate the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2021.05.034DOI Listing
July 2021

Geospatial Analysis of Neighborhood Environmental Stress in Relation to Biological Markers of Cardiovascular Health and Health Behaviors in Women: Protocol for a Pilot Study.

JMIR Res Protoc 2021 Jul 22;10(7):e29191. Epub 2021 Jul 22.

Social Determinants of Obesity and Cardiovascular Risk Laboratory, Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States.

Background: Innovative analyses of cardiovascular (CV) risk markers and health behaviors linked to neighborhood stressors are essential to further elucidate the mechanisms by which adverse neighborhood social conditions lead to poor CV outcomes. We propose to objectively measure physical activity (PA), sedentary behavior, and neighborhood stress using accelerometers, GPS, and real-time perceived ecological momentary assessment via smartphone apps and to link these to biological measures in a sample of White and African American women in Washington, DC, neighborhoods.

Objective: The primary aim of this study is to test the hypothesis that living in adverse neighborhood social conditions is associated with higher stress-related neural activity among 60 healthy women living in high or low socioeconomic status neighborhoods in Washington, DC. Sub-aim 1 of this study is to test the hypothesis that the association is moderated by objectively measured PA using an accelerometer. A secondary objective is to test the hypothesis that residing in adverse neighborhood social environment conditions is related to differences in vascular function. Sub-aim 2 of this study is to test the hypothesis that the association is moderated by objectively measured PA. The third aim of this study is to test the hypothesis that adverse neighborhood social environment conditions are related to differences in immune system activation.

Methods: The proposed study will be cross-sectional, with a sample of at least 60 women (30 healthy White women and 30 healthy Black women) from Wards 3 and 5 in Washington, DC. A sample of the women (n=30) will be recruited from high-income areas in Ward 3 from census tracts within a 15% of Ward 3's range for median household income. The other participants (n=30) will be recruited from low-income areas in Wards 5 from census tracts within a 15% of Ward 5's range for median household income. Finally, participants from Wards 3 and 5 will be matched based on age, race, and BMI. Participants will wear a GPS unit and accelerometer and report their stress and mood in real time using a smartphone. We will then examine the associations between GPS-derived neighborhood variables, stress-related neural activity measures, and adverse biological markers.

Results: The National Institutes of Health Institutional Review Board has approved this study. Recruitment will begin in the summer of 2021.

Conclusions: Findings from this research could inform the development of multilevel behavioral interventions and policies to better manage environmental factors that promote immune system activation or psychosocial stress while concurrently working to increase PA, thereby influencing CV health.

International Registered Report Identifier (irrid): PRR1-10.2196/29191.
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http://dx.doi.org/10.2196/29191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367127PMC
July 2021

Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes.

Endocrinol Diabetes Metab 2021 Jul 9;4(3):e00261. Epub 2021 May 9.

Saha Cardiovascular Research Center University of Kentucky Lexington KY USA.

Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown.

Objective: To determine the effect of metformin on the HDL proteome.

Subjects: Youth (12-20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5.

Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin ( = 25) or placebo ( = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined.

Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%,  = .0058) and alpha-2-macroglobulin (A2MG; +29.8%,  = .049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC.

Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.
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http://dx.doi.org/10.1002/edm2.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279605PMC
July 2021

Chronic inflammatory diseases and coronary heart disease: Insights from cardiovascular CT.

J Cardiovasc Comput Tomogr 2021 Jun 24. Epub 2021 Jun 24.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Epidemiological and clinical studies have demonstrated a consistent relationship between increased systemic inflammation and increased risk of cardiovascular events. In chronic inflammatory states, traditional risk factors only partially account for the development of coronary artery disease (CAD) but underestimate total cardiovascular risk likely due to the residual risk of inflammation. Computed coronary tomography angiography (CCTA) may aid in risk stratification by noninvasively capturing early CAD, identifying high risk plaque morphology and quantifying plaque at baseline and in response to treatment. In this review, we focus on reviewing studies on subclinical atherosclerosis by CCTA in individuals with chronic inflammatory conditions including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), human immunodeficiency virus (HIV) infection and psoriasis. We start with a brief review on the role of inflammation in atherosclerosis, highlight the utility of using CCTA to delineate vessel wall and plaque characteristics and discuss combining CCTA with laboratory studies and emerging technologies to complement traditional risk stratification in chronic inflammatory states.
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http://dx.doi.org/10.1016/j.jcct.2021.06.003DOI Listing
June 2021

A neurobiological link between transportation noise exposure and metabolic disease in humans.

Psychoneuroendocrinology 2021 Sep 17;131:105331. Epub 2021 Jun 17.

Cardiac Imaging Research Center, Massachusetts General Hospital, 165 Cambridge St., Suite 400, Boston, MA 02114, USA; Cardiology Division, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA. Electronic address:

Background: Chronic transportation noise exposure associates with cardiovascular events through a link involving heightened stress-associated neurobiological activity (as amygdalar metabolic activity, AmygA) on F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG-PET/CT). Increased AmygA also associates with greater visceral adipose tissue (VAT) and type 2 diabetes mellitus (DM). While relationships between noise exposure and VAT and DM have been reported, the underlying mechanisms remain incompletely understood. We tested whether: (1) transportation noise exposure associates with greater (a) baseline and gains in VAT and (b) DM risk, and (2) heightened AmygA partially mediates the link between noise exposure and these metabolic diseases.

Methods: VAT was measured in a retrospective cohort (N = 403) who underwent clinical F-FDG-PET/CT. AmygA was measured in those with brain imaging (N = 238). Follow-up VAT was remeasured on available imaging (N = 67). Among individuals (N = 224) without baseline DM, incident DM was adjudicated over 2 years from clinical records. Noise (24-h average) was modeled at each individual's home address. Linear regression, survival, and mediation analyses were employed.

Results: Higher noise exposure (upper tertile vs. others) associated with greater: baseline VAT (standardized β [95% confidence interval (CI)]= 0.230 [0.021, 0.438], p = 0.031), gains in VAT (0.686 [0.185, 1.187], p = 0.008 adjusted for baseline VAT), and DM (hazard ratio [95% CI]=2.429 [1.031, 5.719], p = 0.042). The paths of: ↑noise exposure→↑AmygA→↑baseline VAT and ↑noise exposure→↑AmygA→↑subsequent DM were significant (p < 0.05).

Conclusions: Increased transportation noise exposure associates with greater VAT and DM. This relationship is partially mediated by stress-associated neurobiological activity. These findings suggest altered neurobiology contributes to noise exposure's link to metabolic diseases.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405593PMC
September 2021

Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.

Nat Commun 2021 06 7;12(1):3391. Epub 2021 Jun 7.

Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.
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http://dx.doi.org/10.1038/s41467-021-23361-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185103PMC
June 2021

The relationship between TNF-alpha driven inflammation, lipids and endothelial function in rheumatoid arthritis: a complex puzzle continues.

Cardiovasc Res 2021 Jun 4. Epub 2021 Jun 4.

Section of Inflammation and Cardiovascular Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1093/cvr/cvab190DOI Listing
June 2021

Impact of Biological Agents on Imaging and Biomarkers of Cardiovascular Disease in Patients with Psoriasis: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

J Invest Dermatol 2021 Apr 21. Epub 2021 Apr 21.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Background: The effect of biologics on the risk for cardiovascular disease in patients with psoriasis is still unclear despite their widespread use.

Objective: The objective of this study was to examine the impact of licensed biological therapies on imaging and biomarkers of cardiovascular disease risk in patients with psoriasis by a systematic review and meta-analysis of placebo-controlled trials.

Methods: A comprehensive search of studies published before 1 June 2020 was performed in Medline-Ovid, EMBASE, and CENTRAL using a predefined strategy to identify relevant articles.

Results: Five studies were included for the final examination, and two studies were included in the meta-analysis. We did not find a significant reduction in aortic vascular inflammation in patients treated with adalimumab compared with those who received placebo at weeks 12-16. There was no beneficial effect on imaging biomarkers (aortic vascular inflammation or flow-mediated dilatation) of cardiovascular disease risk in patients exposed to biological therapies (adalimumab and secukinumab) compared with those exposed to placebo, except for ustekinumab showing a reduction in aortic vascular inflammation at week 12 but not at week 52 after the open-label extension period. The strongest reduction in blood-based cardiometabolic risk biomarkers was observed with adalimumab (CRP, TNF-α, IL-6, and GlycA) and phototherapy (CRP and IL-6) compared with that observed with placebo.

Conclusions: Randomized controlled trials show that ustekinumab reduces aortic vascular inflammation and that TNF-α inhibitors and phototherapy reduce CRP and IL-6. These surrogate marker findings require randomized controlled trials evaluating cardiovascular events to inform clinical practice.
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http://dx.doi.org/10.1016/j.jid.2021.03.024DOI Listing
April 2021

New Frontiers in Psoriatic Disease Research, Part II: Comorbidities and Targeted Therapies.

J Invest Dermatol 2021 Apr 19. Epub 2021 Apr 19.

Department of Dermatology, University of California San Francisco, San Francisco, California. Electronic address:

Although psoriasis and psoriatic arthritis (PsA) have been classically considered to be diseases of the skin and joints, respectively, emerging evidence suggests that a combination of innate and environmental factors creates widespread immune dysfunction, affecting multiple organ systems. A greater understanding of the pathogenesis of psoriasis and the systemic effects of psoriatic inflammation has allowed for the development of new, more effective treatments. The second portion of this two-part review series examines the comorbidities associated with psoriasis and PsA as well as the most recent advances in targeted systemic therapies for these conditions.
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http://dx.doi.org/10.1016/j.jid.2021.02.743DOI Listing
April 2021

Epicardial Assessment of Coronary Artery Disease in Inflammatory Diseases: Is it Enough?

Authors:
Nehal N Mehta

JACC Cardiovasc Imaging 2021 Apr 7. Epub 2021 Apr 7.

Lab of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2021.02.013DOI Listing
April 2021

The evolving role of coronary CT angiography in Acute Coronary Syndromes.

J Cardiovasc Comput Tomogr 2021 Sep-Oct;15(5):384-393. Epub 2021 Feb 23.

Division of Cardiology, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

In the United States, non-obstructive coronary disease has been on the rise, and each year, nearly one million adults suffer myocardial infarction, 70% of which are non-ST-segment elevation myocardial infarction (NSTEMI). In addition, approximately 15% of patients suffering NSTEMI will have subsequent readmission for a recurrent acute coronary syndrome (ACS). While invasive angiography remains the standard of care in the diagnostic and therapeutic approach to these patients, these methods have limitations that include procedural complications, uncertain specificity in diagnosis of the culprit lesion in patients with multi-vessel coronary artery disease (CAD), and challenges in following coronary disease over time. The role of coronary computed tomography angiography (CCTA) for evaluating patients with both stable and acute chest pain has seen a paramount upshift in the last decade. This paper reviews the established role of CCTA for the rapid exclusion of obstructive plaque in troponin negative acute chest pain, while exploring opportunities to address challenges in the current approach to evaluating NSTEMI.
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http://dx.doi.org/10.1016/j.jcct.2021.02.002DOI Listing
February 2021

FDG-PET in ischemic strokes of unknown origin: Have we found the needle in the haystack?

J Nucl Cardiol 2021 Apr 6. Epub 2021 Apr 6.

Lab of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, Bethesda, MD, 20892, USA.

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http://dx.doi.org/10.1007/s12350-021-02598-7DOI Listing
April 2021

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in a Community-Based Cohort: Data From the Washington, D.C. Cardiovascular Health and Needs Assessment.

Front Cardiovasc Med 2021 10;8:599341. Epub 2021 Mar 10.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, United States.

Psychosocial stress correlates with cardiovascular (CV) events; however, associations between physiologic measures of stressors and CVD remain incompletely understood, especially in racial/ethnic minority populations in resource-limited neighborhoods. We examined associations between chronic stress-related neural activity, measured by amygdalar Fluorodeoxyglucose (FDG) uptake, and aortic vascular FDG uptake (arterial inflammation measure) in a community-based cohort. Forty participants from the Washington, DC CV Health and Needs Assessment (DC-CHNA), a study of a predominantly African-American population in resource-limited urban areas and 25 healthy volunteers underwent detailed phenotyping, including FDG PET/CT for assessing amygdalar activity (AmygA), vascular FDG uptake, and hematopoietic (leukopoietic) tissue activity. Mediation analysis was used to test whether the link between AmygA and vascular FDG uptake was mediated by hematopoietic activity. AmygA (1.11 ± 0.09 vs. 1.05 ± 0.09, = 0.004) and vascular FDG uptake (1.63 ± 0.22 vs. 1.55 ± 0.17, = 0.05) were greater in the DC-CHNA cohort compared to volunteers. Within the DC-CHNA cohort, AmygA associated with vascular FDG uptake after adjustment for Framingham score and body mass index (β = 0.41, = 0.015). The AmygA and aortic vascular FDG uptake relationship was in part mediated by splenic (20.2%) and bone marrow (11.8%) activity. AmygA, or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort. This may in part be mediated by the hematopoietic system. Our findings of this hypothesis-generating study are suggestive of a potential relationship between chronic stress-related neural activity and subclinical CVD in an African American community-based population. Taken together, these findings suggest a potential mechanism by which chronic psychosocial stress, such as stressors that can be experienced in adverse social conditions, promotes greater cardiovascular risk amongst resource-limited, community-based populations most impacted by cardiovascular health disparities. However, larger prospective studies examining these findings in other racially and ethnically diverse populations are necessary to confirm and extend these findings.
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http://dx.doi.org/10.3389/fcvm.2021.599341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988194PMC
March 2021

Fasting-induced FOXO4 blunts human CD4 T helper cell responsiveness.

Nat Metab 2021 03 15;3(3):318-326. Epub 2021 Mar 15.

Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Intermittent fasting blunts inflammation in asthma and rheumatoid arthritis, suggesting that fasting may be exploited as an immune-modulatory intervention. However, the mechanisms underpinning the anti-inflammatory effects of fasting are poorly characterized. Here, we show that fasting in humans is sufficient to blunt CD4 T helper cell responsiveness. RNA sequencing and flow cytometry immunophenotyping of peripheral blood mononuclear cells from volunteers subjected to overnight or 24-h fasting and 3 h of refeeding suggest that fasting blunts CD4 T helper cell activation and differentiation. Transcriptomic analysis reveals that longer fasting has a more robust effect on CD4 T-cell biology. Through bioinformatics analyses, we identify the transcription factor FOXO4 and its canonical target FK506-binding protein 5 (FKBP5) as a potential fasting-responsive regulatory axis. Genetic gain- or loss-of-function of FOXO4 and FKBP5 is sufficient to modulate T1 and T17 cytokine production. Moreover, we find that fasting-induced or genetic overexpression of FOXO4 and FKBP5 is sufficient to downregulate mammalian target of rapamycin complex 1 signalling and suppress signal transducer and activator of transcription 1/3 activation. Our results identify FOXO4-FKBP5 as a new fasting-induced, signal transducer and activator of transcription-mediated regulatory pathway to blunt human CD4 T helper cell responsiveness.
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http://dx.doi.org/10.1038/s42255-021-00356-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990708PMC
March 2021

Application of machine learning in understanding atherosclerosis: Emerging insights.

APL Bioeng 2021 Mar 16;5(1):011505. Epub 2021 Feb 16.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Biological processes are incredibly complex-integrating molecular signaling networks involved in multicellular communication and function, thus maintaining homeostasis. Dysfunction of these processes can result in the disruption of homeostasis, leading to the development of several disease processes including atherosclerosis. We have significantly advanced our understanding of bioprocesses in atherosclerosis, and in doing so, we are beginning to appreciate the complexities, intricacies, and heterogeneity atherosclerosi. We are also now better equipped to acquire, store, and process the vast amount of biological data needed to shed light on the biological circuitry involved. Such data can be analyzed within machine learning frameworks to better tease out such complex relationships. Indeed, there has been an increasing number of studies applying machine learning methods for patient risk stratification based on comorbidities, multi-modality image processing, and biomarker discovery pertaining to atherosclerotic plaque formation. Here, we focus on current applications of machine learning to provide insight into atherosclerotic plaque formation and better understand atherosclerotic plaque progression in patients with cardiovascular disease.
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http://dx.doi.org/10.1063/5.0028986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889295PMC
March 2021

Underperformance of clinical risk scores in identifying imaging-based high cardiovascular risk in psoriasis: results from two observational cohorts.

Eur J Prev Cardiol 2020 Nov 9. Epub 2020 Nov 9.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Clinical Research Center, Room 5-5140, Bethesda, MD 20892, USA.

Aims: We aimed to evaluate whether traditional risk scores [short-term, 'psoriasis-modified' (multiplied by 1.5) and lifetime] were able to capture high cardiovascular disease (CVD) risk as defined by the presence of atherosclerotic plaques in coronary, femoral, or carotid arteries in psoriasis.

Methods And Results: We used two prospectives obseravational cohorts. European cohort: femoral and carotid atherosclerotic plaques were evaluated by ultrasound in 73 psoriasis patients. Lifetime CVD risk (LTCVR) was evaluated with QRISK-LT; short-term CVD risk was evaluated with SCORE and psoriasis-modified SCORE. American cohort: 165 patients underwent coronary computed tomography angiography to assess presence of coronary plaques. LTCVR was evaluated with atherosclerotic cardiovascular disease (ASCVD-LT) lifetime; short-term CVD risk was evaluated with ASCVD and psoriasis-modified ASCVD. European cohort: subclinical atherosclerosis was present in 51% of patients. QRISK-LT identified 64% of patients with atherosclerosis missing a high proportion (35%) with atheroma plaque (P < 0.05). The percentage of patients with atherosclerosis identified by QRISK-LT was significantly higher than those detected by SCORE (0%) and modified SCORE (10%). American cohort: subclinical atherosclerosis was present in 54% of patients. ASCVD-LT captured 54% of patients with coronary plaques missing a high proportion (46%) with coronary plaque (P < 0.05). The percentage of patients with atheroma plaques detected with ASCVD and modified ASCVD were only 20% and 45%, respectively.

Conclusions: Application of lifetime, short-term and 'psoriasis-modified' risk scores did not accurately capture psoriasis patients at high CVD risk.
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http://dx.doi.org/10.1093/eurjpc/zwaa033DOI Listing
November 2020

Divergence of Cardiovascular Biomarkers of Lipids and Subclinical Myocardial Injury Among Rheumatoid Arthritis Patients With Increased Inflammation.

Arthritis Rheumatol 2021 06 9;73(6):970-979. Epub 2021 May 9.

Brigham and Women's Hospital, Harvard Medical School, and VA Boston Healthcare System, Boston, Massachusetts.

Objective: Patients with rheumatoid arthritis (RA) are 1.5 times more likely to develop cardiovascular disease (CVD) attributed to chronic inflammation. A decrease in inflammation in patients with RA is associated with increased low-density lipoprotein (LDL) cholesterol. This study was undertaken to prospectively evaluate the changes in lipid levels among RA patients experiencing changes in inflammation and determine the association with concomitant temporal patterns in markers of myocardial injury.

Methods: A total of 196 patients were evaluated in a longitudinal RA cohort, with blood samples and high-sensitivity C-reactive protein (hsCRP) levels measured annually. Patients were stratified based on whether they experienced either a significant increase in inflammation (an increase in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the increased inflammation cohort [n = 103]) or decrease in inflammation (a decrease in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the decreased inflammation cohort [n = 93]). Routine and advanced lipids, markers of inflammation (interleukin-6, hsCRP, soluble tumor necrosis factor receptor II), and markers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro-brain natriuretic peptide) were measured.

Results: Among the patients in the increased inflammation cohort, the mean age was 59 years, 81% were women, and the mean RA disease duration was 17.9 years. The average increase in hsCRP levels was 36 mg/liter, and this increase was associated with significant reductions in LDL cholesterol, triglycerides, total cholesterol, apolipoprotein (Apo B), and Apo A-I levels. In the increased inflammation cohort at baseline, 45.6% of patients (47 of 103) had detectable circulating hs-cTnT, which further increased during inflammation (P = 0.02). In the decreased inflammation cohort, hs-cTnT levels remained stable despite a reduction in inflammation over follow-up. In both cohorts, hs-cTnT levels were associated with the overall estimated risk of CVD.

Conclusion: Among RA patients who experienced an increase in inflammation, a significant decrease in routinely measured lipids, including LDL cholesterol, and an increase in markers of subclinical myocardial injury were observed. These findings highlight the divergence in biomarkers of CVD risk and suggest a role in future studies examining the benefit of including hs-cTnT for CVD risk stratification in RA.
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http://dx.doi.org/10.1002/art.41613DOI Listing
June 2021

Nanotomography of lesional skin using electron microscopy reveals cytosolic release of nuclear DNA in psoriasis.

JAAD Case Rep 2021 Mar 6;9:9-14. Epub 2021 Jan 6.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.jdcr.2020.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868746PMC
March 2021

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.

Eur Heart J 2021 03;42(9):896-903

Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiovascular Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215, USA.

Aims: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy.

Methods And Results: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001).

Conclusion: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab.
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http://dx.doi.org/10.1093/eurheartj/ehaa1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936519PMC
March 2021

Association of neutrophil-to-lymphocyte ratio with non-calcified coronary artery burden in psoriasis: Findings from an observational cohort study.

J Cardiovasc Comput Tomogr 2021 Jul-Aug;15(4):372-379. Epub 2020 Dec 28.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Inflammation in the form of elevated high-sensitivity c-reactive protein (hs-CRP) has been shown to be critical in the development of atherothrombosis. Psoriasis, a chronic inflammatory skin disease, is associated with high systemic-inflammation, elevated neutrophil-to-lymphocyte ratio (NLR) and accelerated non-calcified coronary artery burden (NCB) by coronary computed tomography angiography (CCTA). We hypothesized that NLR would associate with early, rupture-prone atherosclerosis assessed as NCB independent of hs-CRP.

Methods: 316 consecutive psoriasis participants were recruited with 233 having one-year follow-up as part of a prospective, observational cohort study design. CCTA scans were performed to assess NCB in all three major epicardial coronary arteries.

Results: Patients with above average NLR (>mean: 2.29 ​± ​1.21) were older (mean ​± ​SD; 52.0 ​± ​12.8 vs. 47.9 ​± ​12.6, p ​= ​0.002), had higher hs-CRP (med. IQR: 2.3 (0.9-7.3) vs. 1.4 (0.7-3.2), p ​= ​0.001) and had higher NCB (mean ​± ​SD; 1.21 ​± ​0.58 vs. 1.13 ​± ​0.49, p ​= ​0.018) when compared to patients with below average NLR. NLR associated with psoriasis area severity index score (β ​= ​0.14, p ​= ​0.017), hs-CRP (β ​= ​0.16, p ​= ​0.005), as well as NCB independent of traditional risk factors, body mass index, statin use and hs-CRP (β ​= ​0.08, p ​= ​0.009). One year of biologic therapy for psoriasis was associated with a reduction in NLR (-14.5%, p ​< ​0.001), and this change in NLR associated with change in NCB in fully adjusted models and beyond hs-CRP (β ​= ​0.17, p ​= ​0.002).

Conclusion: NLR associated with psoriasis severity, hs-CRP and NCB at baseline. Biologic therapy reduced NLR over time and this change in NLR associated with the change in NCB at one-year. Taken together, these findings suggest that NLR may capture psoriasis patients at higher risk of NCB due to residual inflammation not fully captured by hs-CRP.
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http://dx.doi.org/10.1016/j.jcct.2020.12.006DOI Listing
December 2020

Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis.

J Invest Dermatol 2021 Jun 30;141(6):1493-1502. Epub 2020 Dec 30.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor Michigan, USA. Electronic address:

Psoriasis and type 2 diabetes (T2D) are complex conditions with significant impacts on health. Patients with psoriasis have a higher risk of T2D (∼1.5 OR) and vice versa, controlling for body mass index; yet, there has been a limited study comparing their genetic architecture. We hypothesized that there are shared genetic components between psoriasis and T2D. Trans-disease meta-analysis was applied to 8,016,731 well-imputed genetic markers from large-scale meta-analyses of psoriasis (11,024 cases and 16,336 controls) and T2D (74,124 cases and 824,006 controls), adjusted for body mass index. We confirmed our findings in a hospital-based study (42,112 patients) and tested for causal relationships with multivariable Mendelian randomization. Mendelian randomization identified a causal relationship between psoriasis and T2D (P = 1.6 × 10, OR = 1.01) and highlighted the impact of body mass index. Trans-disease meta-analysis further revealed four genome-wide significant loci (P < 5 × 10) with evidence of colocalization and shared directions of effect between psoriasis and T2D not present in body mass index. The proteins coded by genes in these loci (ACTR2, ERLIN1, TRMT112, and BECN1) are connected through NF-κB signaling. Our results provide insight into the immunological components that connect immune-mediated skin conditions and metabolic diseases, independent of confounding factors.
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http://dx.doi.org/10.1016/j.jid.2020.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154633PMC
June 2021

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

J Am Acad Dermatol 2021 May 3;84(5):1329-1338. Epub 2021 Feb 3.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

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 (β = .31; P < .001) and its individual factors of waist circumference (β = .33; P < .001), triglyceride levels (β = .17; P = .005), blood pressure (β = .18; P = .005), and fasting glucose (β = .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.
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http://dx.doi.org/10.1016/j.jaad.2020.12.044DOI Listing
May 2021

Inflammatory Bowel Disease and Atherosclerotic Cardiovascular Disease: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 12;76(24):2895-2905

Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston, Texas, USA; Center for Outcomes Research, Houston Methodist, Houston, Texas, USA. Electronic address:

Chronic inflammatory diseases including human immunodeficiency virus infection, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus predispose to atherosclerotic cardiovascular disease (ASCVD). Inflammatory bowel disease (IBD) is a common chronic inflammatory condition, and the United States has the highest prevalence worldwide. IBD has so far been overlooked as a contributor to the burden of ASCVD among young and middle-age adults, but meta-analyses of cohort studies suggest that IBD is an independent risk factor for ASCVD. This review discusses the epidemiological links between IBD and ASCVD and potential mechanisms underlying these associations. ASCVD risk management of patients with IBD is challenging because of their young age and the inability of current risk scores to fully capture their increased risk. The role of IBD in current primary prevention guidelines is evaluated, and strategies for enhanced ASCVD risk reduction in patients with IBD are outlined. Finally, the authors discuss knowledge gaps and future research directions in this innovative field.
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http://dx.doi.org/10.1016/j.jacc.2020.10.027DOI Listing
December 2020

The application of molecular imaging to advance translational research in chronic inflammation.

J Nucl Cardiol 2020 Nov 26. Epub 2020 Nov 26.

National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.

Over the past several decades, molecular imaging techniques to assess cellular processes in vivo have been integral in advancing our understanding of disease pathogenesis. F-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) imaging in particular has shaped the field of atherosclerosis research by highlighting the importance of underlying inflammatory processes that are responsible for driving disease progression. The ability to assess physiology using molecular imaging, combining it with anatomic delineation using cardiac coronary angiography (CCTA) and magnetic resonance imaging (MRI) and lab-based techniques, provides a powerful combination to advance both research and ultimately clinical care. In this review, we demonstrate how molecular imaging studies, specifically using 18-FDG PET, have revealed that early vascular disease is a systemic process with multiple, concurrent biological mechanisms using inflammatory diseases as a basis to understand early atherosclerotic mechanisms in humans.
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http://dx.doi.org/10.1007/s12350-020-02439-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149483PMC
November 2020

Association Between Early Severe Cardiovascular Events and Ustekinumab Treatment?

JAMA Dermatol 2021 01;157(1):123

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamadermatol.2020.4456DOI Listing
January 2021
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