Mark A. Ahlman

Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study

Objective—To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography computed tomography. Approach—In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using 18F-fluorodeoxyglucose positron emission tomography computed tomography. Results—Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8–8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (&bgr;=0.41, P=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2; P=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL; P<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL; P<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (&bgr;=0.53; P=0.02) and vascular inflammation (&bgr;=0.48; P=0.02). Conclusions—Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.

GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis

RATIONALE GlycA, an emerging inflammatory biomarker, predicted cardiovascular events in population-based studies. Psoriasis, an inflammatory disease associated with increased cardiovascular risk, provides a model to study inflammatory biomarkers in cardiovascular disease (CVD). Whether GlycA associates with psoriasis and how it predicts subclinical CVD beyond high-sensitivity C-reactive protein in psoriasis is unknown. OBJECTIVE To investigate the relationships between GlycA and psoriasis and between GlycA and subclinical CVD. METHODS AND RESULTS Patients with psoriasis and controls (n=412) participated in a 2-stage study. We measured GlycA by nuclear magnetic resonance spectroscopy. National Institutes of Health (NIH) participants underwent 18-F Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (18-FDG PET/CT) scans to assess vascular inflammation (VI) and coronary computed tomographic angiography to quantify coronary artery disease burden. Psoriasis cohorts were young (mean age=47.9), with low cardiovascular risk and moderate skin disease. high-sensitivity C-reactive protein and GlycA were increased in psoriasis compared with controls (GlycA: [PENN: 408.8±75.4 versus 289.4±60.2, P<0.0001; NIH: 415.8±63.2 versus 346.2±46, P<0.0001]) and demonstrated a dose-response with psoriasis severity. In stage 2, VI (β=0.36, P<0.001) and coronary artery disease (β=0.29, P=0.004) associated with GlycA beyond CV risk factors in psoriasis. In receiver operating characteristic analysis, GlycA added value in predicting VI (P=0.01) and coronary artery disease (P<0.01). Finally, initiating anti-tumor necrosis factor therapy (n=16) reduced psoriasis severity (P<0.001), GlycA (463.7±92.5 versus 370.1±78.5, P<0.001) and VI (1.93±0.36 versus 1.76±0.19, P<0.001), whereas GlycA remained associated with VI (β=0.56, P<0.001) post treatment. CONCLUSIONS GlycA associated with psoriasis severity and subclinical CVD beyond traditional CV risk and high-sensitivity C-reactive protein. Moreover, psoriasis treatment reduced GlycA and VI. These findings support the potential use of GlycA in subclinical CVD risk assessment in psoriasis and potentially other inflammatory diseases.

Accelerated acquisition of tagged MRI for cardiac motion correction in simultaneous PET-MR: Phantom and patient studies

PURPOSE Degradation of image quality caused by cardiac and respiratory motions hampers the diagnostic quality of cardiac PET. It has been shown that improved diagnostic accuracy of myocardial defect can be achieved by tagged MR (tMR) based PET motion correction using simultaneous PET-MR. However, one major hurdle for the adoption of tMR-based PET motion correction in the PET-MR routine is the long acquisition time needed for the collection of fully sampled tMR data. In this work, the authors propose an accelerated tMR acquisition strategy using parallel imaging and/or compressed sensing and assess the impact on the tMR-based motion corrected PET using phantom and patient data. METHODS Fully sampled tMR data were acquired simultaneously with PET list-mode data on two simultaneous PET-MR scanners for a cardiac phantom and a patient. Parallel imaging and compressed sensing were retrospectively performed by GRAPPA and kt-FOCUSS algorithms with various acceleration factors. Motion fields were estimated using nonrigid B-spline image registration from both the accelerated and fully sampled tMR images. The motion fields were incorporated into a motion corrected ordered subset expectation maximization reconstruction algorithm with motion-dependent attenuation correction. RESULTS Although tMR acceleration introduced image artifacts into the tMR images for both phantom and patient data, motion corrected PET images yielded similar image quality as those obtained using the fully sampled tMR images for low to moderate acceleration factors (<4). Quantitative analysis of myocardial defect contrast over ten independent noise realizations showed similar results. It was further observed that although the image quality of the motion corrected PET images deteriorates for high acceleration factors, the images were still superior to the images reconstructed without motion correction. CONCLUSIONS Accelerated tMR images obtained with more than 4 times acceleration can still provide relatively accurate motion fields and yield tMR-based motion corrected PET images with similar image quality as those reconstructed using fully sampled tMR data. The reduction of tMR acquisition time makes it more compatible with routine clinical cardiac PET-MR studies.

Coronary Plaque Burden at Coronary CT Angiography in Asymptomatic Men and Women

Purpose To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk. Materials and Methods This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320-detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes. Results The mean age of the subjects was 65.5 years ± 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1-434). The total coronary plaque index was higher in men than in women (42.06 mm(2) ± 9.22 vs 34.33 mm(2) ± 8.35; P < .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm(2); P = .03) and in those with higher simvastatin doses (by 0.44 mm(2)/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (β = 0.80 mm(2)/10 mm Hg; P = .03), diabetes (β = 4.47 mm(2); P = .03), and low-density lipoprotein (LDL) cholesterol level (β = 0.04 mm(2)/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score. Conclusion LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk. (©) RSNA, 2015 Online supplemental material is available for this article.

Cardiac and respiratory motion correction for simultaneous cardiac PET-MR

Cardiac PET is a versatile imaging technique providing important diagnostic information about ischemic heart diseases. Respiratory and cardiac motion of the heart can strongly impair image quality and therefore diagnostic accuracy of cardiac PET scans. The aim of this study was to investigate a new cardiac PET/MR approach providing respiratory and cardiac motion–compensated MR and PET images in less than 5 min. Methods: Free-breathing 3-dimensional MR data were acquired and retrospectively binned into multiple respiratory and cardiac motion states. Three-dimensional cardiac and respiratory motion fields were obtained with a nonrigid registration algorithm and used in motion-compensated MR and PET reconstructions to improve image quality. The improvement in image quality and diagnostic accuracy of the technique was assessed in simultaneous 18F-FDG PET/MR scans of a canine model of myocardial infarct and was demonstrated in a human subject. Results: MR motion fields were successfully used to compensate for in vivo cardiac motion, leading to improvements in full width at half maximum of the canine myocardium of 13% ± 5%, similar to cardiac gating but with a 90% ± 57% higher contrast-to-noise ratio between myocardium and blood. Motion correction led to an improvement in MR image quality in all subjects, with an increase in sharpness of the canine coronary arteries of 85% ± 72%. A functional assessment showed good agreement with standard MR cine scans with a difference in ejection fraction of −2% ± 3%. MR-based respiratory and cardiac motion information was used to improve the PET image quality of a human in vivo scan. Conclusion: The MR technique presented here provides both diagnostic and motion information that can be used to improve MR and PET image quality. Reliable respiratory and cardiac motion correction could make cardiac PET results more reproducible.

Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography

Importance Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases. Objective To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti–tumor necrosis factor therapy on vascular inflammation. Design, Setting, and Participants In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016. Exposure Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score. Main Outcomes and Measures Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography. Results Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti–tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (&bgr; = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti–tumor necrosis factor therapy (&bgr; = 0.79; 95% CI, 0.269-1.311; P = .03). Conclusions and Relevance Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.

18F-Fluorodeoxyglucose–Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis

To assess the clinical value of 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large vessel vasculitis (LVV) and comparator subjects.

The relationship between duration of psoriasis, vascular inflammation, and cardiovascular events

Background: Psoriasis is associated with risk of cardiovascular (CV) disease (CVD) and a major adverse CV event (MACE). Whether psoriasis duration affects risk of vascular inflammation and MACEs has not been well characterized. Objectives: We utilized two resources to understand the effect of psoriasis duration on vascular disease and CV events: (1) a human imaging study and (2) a population‐based study of CVD events. Methods: First, patients with psoriasis (N = 190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography (duration effect reported as a &bgr;‐coefficient). Second, MACE risk was examined by using nationwide registries (adjusted hazard ratios in patients with psoriasis (n = 87,161) versus the general population (n = 4,234,793). Results: In the human imaging study, patients were young, of low CV risk by traditional risk scores, and had a high prevalence of cardiometabolic diseases. Vascular inflammation by fludeoxyglucose F 18 positron emission tomography/computed tomography was significantly associated with disease duration (&bgr; = 0.171, P = .002). In the population‐based study, psoriasis duration had strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007‐1.013]). Limitations: These studies utilized observational data. Conclusion: We found detrimental effects of psoriasis duration on vascular inflammation and MACE, suggesting that cumulative duration of exposure to low‐grade chronic inflammation may accelerate vascular disease development and MACEs. Providers should consider inquiring about duration of disease to counsel for heightened CVD risk in psoriasis.

PD-1 Blockade in Mediastinal Gray-Zone Lymphoma

Mediastinal gray-zone lymphoma is intermediate between classic Hodgkin’s lymphoma and primary mediastinal B-cell lymphoma. Three patients whose disease had become refractory to chemotherapy had impressive responses to PD-1 blockade.

A new twist on an old idea: a two-dimensional speckle tracking assessment of cyclosporine as a therapeutic alternative for heart failure with preserved ejection fraction

We recently reported that mitochondrial dysfunction, characterized by increased mitochondrial permeability transition (MPT), was present in a translational swine model of heart failure with preserved ejection fraction (HFpEF). Cyclophilin D is a key component of the MPT pore, therefore, the purpose of this study was to test the efficacy of a novel cyclosporine (CsA) dosing scheme as a therapeutic alternative for HFpEF. Computed tomography (CT), two‐dimensional speckle tracking two‐dimensional speckle tracking (2DST), and invasive hemodynamics were used to evaluate cardiac function. CT imaging showed 14 weeks of CsA treatment caused eccentric myocardial remodeling (contrasting concentric remodeling in untreated HF animals) and elevated systemic pressures. 2DST detected left ventricular (LV) mechanics associated with systolic and diastolic dysfunction prior to the onset of significantly increased LV end diastolic pressure including: (1) decreased systolic apical rotation rate, longitudinal displacement, and longitudinal/radial/circumferential strain; (2) decreased early diastolic untwisting and longitudinal strain rate; and (3) increased late diastolic radial/circumferential mitral strain rate. LV mechanics associated with systolic and diastolic impairment was enhanced to a greater extent than seen in untreated HF animals following CsA treatment. In conclusion, CsA treatment accelerated the development of heart failure, including dilatory LV remodeling and impaired systolic and diastolic mechanics. Although our findings do not support CsA as a viable therapy for HFpEF, 2DST was effective in differentiating between progressive gradations of developing HF and detecting diastolic impairment prior to the development of overt diastolic dysfunction.