Association Between Aortic Vascular Inflammation and Coronary Artery Plaque Characteristics in Psoriasis

Joshi, Aditya; Lerman, Joseph B; Dey, Amit; Sajja, Aparna; Belur, Agastya D.; Elnabawi, Youssef; Rodante, Justin; Aberra, Tsion; Chung, Jonathan; Salahuddin, Taufiq; Natarajan, Balaji; Dave, Jenny; Goyal, Aditya; Groenendyk, Jacob; Rivers, Joshua; Baumer, Yvonne; Teague, Heather; Playford, Martin P.; Bluemke, David A.; Ahlman, Mark A.; Chen, Marcus Y; Gelfand, Joel M.; Mehta, Nehal N.

doi:10.1001/jamacardio.2018.2769

Cited by 57 publications

(39 citation statements)

References 40 publications

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“…Despite the well-established methods used for quantification, PET imaging itself has limitations, which include the selection of background tissue for correction (e.g., blood pool) and which aortic segments were analyzed (e.g., arch vs. entire aorta). Moreover, AVI is not a direct measure of coronary disease, but it has been shown to correlate with presence of noncalcified plaque burden in the coronary artery, supporting the notion that extending these imaging studies to additionally phenotype the coronary artery tree is important (Joshi et al, 2018). Although, our study provides important biologic insights into the effects of targeting IL-12 and IL-23 in humans on key cardiovascular pathways, we are unable to determine if the effects were mediated by IL-12 or IL-23 blockade or both.…”

Section: Discussionmentioning

confidence: 97%

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial)

Gelfand

Shin

Alavi

et al. 2020

Journal of Investigative Dermatology

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Psoriasis is a T helper type 17 autoimmune disease associated with an increased risk cardiovascular events and mortality. Ustekinumab, an antibody to p40, blocks cytokines IL-12 and IL-23, and is a highly effective and safe treatment for psoriasis. We conducted a randomized double-blinded placebo-controlled trial to determine the effect of ustekinumab on aortic vascular inflammation (AVI) measured by imaging, and key biomarkers of inflammation, lipid, and glucose metabolism in the blood of patients with moderate-to-severe psoriasis. A total of 43 patients were randomized, and at week 12, ustekinumab-treated patients had a e18.65% (95% confidence interval ¼ e29.45% to e7.85%) reduction in AVI, a reduction in inflammatory biomarkers, and an increase in apolipoprotein B lipoproteins compared with placebo. At week 12, placebo patients were crossed over such that all patients received ustekinumab for 52 weeks. At the end of 52 weeks of ustekinumab treatment, there was no change in AVI compared with baseline, inflammatory markers were reduced, and there were increases in selected measures of lipids and leptin. These results show that blockade of IL-12 and/or IL-23 may transiently reduce AVI, with more durable reduction in inflammatory cytokines associated with cardiovascular disease.

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Section: Discussionmentioning

confidence: 97%

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial)

Gelfand

Shin

Alavi

et al. 2020

Journal of Investigative Dermatology

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100

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“…Psoriasis is a chronic inflammatory skin disease associated with elevated systemic inflammation, early dyslipidaemia and increased subclinical as well as clinical atherosclerosis in the form of lipid-rich non-calcified coronary disease by coronary computed tomography [ 7 , 8 , 51 ] and incident myocardial infarction. [ 5 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ] In fact, the elevated cardiovascular risk seen in psoriasis patients is in part due to dysregulation of superimposed lipid and inflammatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Hyperlipidaemia and IFNgamma/TNFalpha Synergism are associated with cholesterol crystal formation in Endothelial cells partly through modulation of Lysosomal pH and Cholesterol homeostasis

et al. 2020

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Background Inflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation. Methods We utilized a combination of a mouse psoriasis model ( K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo . Findings We detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p < 0.001). Interpretation Our results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis. Funding Funding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB).

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“…This study has relevance to other disease populations with an increased inflammatory potential such as rheumatoid arthritis. 50 Thus, PWH represent an important population in which to test whether CVD-protective effects of statins is mediated through pleotropic effects on immune activation and inflammation 9,37,51 as well as lipid lowering. REPRIEVE and its Mechanistic Substudy will help to provide information to guide primary CVD prevention for PWH, a population for whom appropriate algorithms for predicting CVD events have not been fully developed and among whom risk stratification is challenging.…”

Section: Discussionmentioning

confidence: 99%

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers

Hoffmann

Olalere

et al. 2019

American Heart Journal

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Association Between Aortic Vascular Inflammation and Coronary Artery Plaque Characteristics in Psoriasis

Abstract: Aortic VI is associated with broad CAD indices, suggesting that aortic VI may be a surrogate for early CAD. Larger prospective studies need to assess these associations longitudinally and examine treatment effects on these outcomes.

Cited by 57 publications

References 40 publications

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial)

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial)

Hyperlipidaemia and IFNgamma/TNFalpha Synergism are associated with cholesterol crystal formation in Endothelial cells partly through modulation of Lysosomal pH and Cholesterol homeostasis

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers

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