Introduction: Cardiac magnetic resonance (CMR) is of diagnostic and prognostic value in a range of cardiopulmonary conditions. Current methods for evaluating CMR studies are laborious and time... Show moreIntroduction: Cardiac magnetic resonance (CMR) is of diagnostic and prognostic value in a range of cardiopulmonary conditions. Current methods for evaluating CMR studies are laborious and time-consuming, contributing to delays for patients. As the demand for CMR increases, there is a growing need to automate this process. The application of artificial intelligence (AI) to CMR is promising, but the evaluation of these tools in clinical practice has been limited. This study assessed the clinical viability of an automatic tool for measuring cardiac volumes on CMR. Methods: Consecutive patients who underwent CMR for any indication between January 2022 and October 2022 at a single tertiary centre were included prospectively. For each case, short-axis CMR images were segmented by the AI tool and manually to yield volume, mass and ejection fraction measurements for both ventricles. Automated and manual measurements were compared for agreement and the quality of the automated contours was assessed visually by cardiac radiologists. Results: 462 CMR studies were included. No statistically significant difference was demonstrated between any automated and manual measurements (p > 0.05; independent T-test). Intraclass correlation coefficient and BlandAltman analysis showed excellent agreement across all metrics (ICC > 0.85). The automated contours were evaluated visually in 251 cases, with agreement or minor disagreement in 229 cases (91.2%) and failed segmentation in only a single case (0.4%). The AI tool was able to provide automated contours in under 90 s. Conclusions: Automated segmentation of both ventricles on CMR by an automatic tool shows excellent agreement with manual segmentation performed by CMR experts in a retrospective real-world clinical cohort. Implementation of the tool could improve the efficiency of CMR reporting and reduce delays between imaging and diagnosis. Show less
Wu, J.P.; Zou, Y.; Meng, X.; Fan, Z.Y.; Geest, R. van der; Cui, F.; ... ; Zhang, F. 2023
ObjectivesCarotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on... Show moreObjectivesCarotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on cervicocerebral computed tomography angiography (CTA) increased the risk of acute ischemic stroke (AIS).MethodsThis retrospective, single-center, cross-sectional study enrolled patients with NRS plaques identified in the subclavian arteries, brachiocephalic trunk, carotid arterial system, and vertebrobasilar circulation on contrast-enhanced cervicocerebral CTA. Patients were divided into AIS and non-AIS groups based on imaging within 12 h of symptom onset. Univariate and multivariate logistic regression analyses were performed to determine the risk factor of AIS occurrence.ResultsA total of 202 patients (66.72 years ± 8.97, 157 men) were evaluated. Plaques with NRS in each subject of the AIS group (N = 98) were significantly more prevalent than that in the control group (N = 104) (1.96 ± 1.17 vs 1.41 ± 0.62). In the AIS group, there were substantially more NRS plaques on the ipsilateral side than contralateral side (1.55 ± 0.90 vs. 0.41 ± 0.66). NRS located on the ipsilateral side of the AIS showed an area under the receiver curve (AUC) of 0.86 to identify ischemic stroke. NRS plaque amounts were an independent risk factor for AIS occurrence (odds ratio, 1.86) after adjusting for other factors.ConclusionsIncreased incidence of napkin-ring sign plaques on cervicocerebral CTA was positively associated with AIS occurrence, which could aid in detecting asymptomatic atherosclerotic patients at high risk of AIS in routine screening or emergency settings. Show less
Kassem, M.; Kam, S.S. de; Velzen, T.J. van; Geest, R. van der; Wagner, B.; Sokolska, M.; ... ; Kooi, M.E. 2023
Purpose: Carotid intraplaque hemorrhage (IPH) on MRI predicts stroke. Magnetization-prepared rapid acquisition gradient (MP-RAGE) is widely used to detect IPH. CE-MRA is used routinely to assess... Show morePurpose: Carotid intraplaque hemorrhage (IPH) on MRI predicts stroke. Magnetization-prepared rapid acquisition gradient (MP-RAGE) is widely used to detect IPH. CE-MRA is used routinely to assess stenosis. Initial studies indicated that IPH can be identified on mask images of CE-MRA, while Time-of-Flight (TOF) images were reported to have high specificity but lower sensitivity. We investigated the diagnostic accuracy of detecting IPH on mask images of CE-MRA and TOF. Methods: Thirty-six patients with >= 50% stenosis enrolled in the ongoing 2nd European Carotid Surgery Trial underwent carotid MRI. A 5-point quality score was used. Inter-observer agreement between two independent readers was determined. The sensitivity and specificity of IPH detection on mask MRA and TOF were calculated with MP-RAGE as a reference standard. Results: Of the 36 patients included in the current analysis, 66/72 carotid arteries could be scored. The interobserver agreements for identifying IPH on MP-RAGE, mask, and TOF were outstanding (K: 0.93, 0.96, and 0.85). The image quality of mask (1.42 +/- 0.66) and TOF (2.42 +/- 0.66) was significantly lower than MP-RAGE (3.47 +/- 0.61). When T1w images were used to delineate the outer carotid wall, very high specificities (>95%) of IPH detection on mask and TOF images were found, while the sensitivity was high for mask images (>81%) and poor for TOF (50–60%). Without these images, the specificity was still high (>97%), while the sensitivity reduced to 62–71%. Conclusion: Despite the lower image quality, routinely acquired mask images from CE-MRA, but not TOF, can be used as an alternative to MP-RAGE images to visualize IPH. Show less
Background Right atrial (RA) area predicts mortality in patients with pulmonary hypertension, and is recommended by the European Society of Cardiology/European Respiratory Society pulmonary... Show moreBackground Right atrial (RA) area predicts mortality in patients with pulmonary hypertension, and is recommended by the European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. The advent of deep learning may allow more reliable measurement of RA areas to improve clinical assessments. The aim of this study was to automate cardiovascular magnetic resonance (CMR) RA area measurements and evaluate the clinical utility by assessing repeatability, correlation with invasive haemodynamics and prognostic value. Methods A deep learning RA area CMR contouring model was trained in a multicentre cohort of 365 patients with pulmonary hypertension, left ventricular pathology and healthy subjects. Inter-study repeatability (intraclass correlation coefficient (ICC)) and agreement of contours (DICE similarity coefficient (DSC)) were assessed in a prospective cohort (n = 36). Clinical testing and mortality prediction was performed in n = 400 patients that were not used in the training nor prospective cohort, and the correlation of automatic and manual RA measurements with invasive haemodynamics assessed in n = 212/400. Radiologist quality control (QC) was performed in the ASPIRE registry, n = 3795 patients. The primary QC observer evaluated all the segmentations and recorded them as satisfactory, suboptimal or failure. A second QC observer analysed a random subcohort to assess QC agreement (n = 1018). Results All deep learning RA measurements showed higher interstudy repeatability (ICC 0.91 to 0.95) compared to manual RA measurements (1st observer ICC 0.82 to 0.88, 2nd observer ICC 0.88 to 0.91). DSC showed high agreement comparing automatic artificial intelligence and manual CMR readers. Maximal RA area mean and standard deviation (SD) DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 is 92.4 +/- 3.5 cm(2), 91.2 +/- 4.5 cm(2) and 93.2 +/- 3.2 cm(2), respectively. Minimal RA area mean and SD DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 was 89.8 +/- 3.9 cm(2), 87.0 +/- 5.8 cm(2) and 91.8 +/- 4.8 cm(2). Automatic RA area measurements all showed moderate correlation with invasive parameters (r = 0.45 to 0.66), manual (r = 0.36 to 0.57). Maximal RA area could accurately predict elevated mean RA pressure low and high-risk thresholds (area under the receiver operating characteristic curve artificial intelligence = 0.82/0.87 vs manual = 0.78/0.83), and predicted mortality similar to manual measurements, both p < 0.01. In the QC evaluation, artificial intelligence segmentations were suboptimal at 108/3795 and a low failure rate of 16/3795. In a subcohort (n = 1018), agreement by two QC observers was excellent, kappa 0.84. Conclusion Automatic artificial intelligence CMR derived RA size and function are accurate, have excellent repeatability, moderate associations with invasive haemodynamics and predict mortality. Show less
Arts, T.; Onkenhout, L.P.; Amier, R.P.; Geest, R. van der; Harten, T. van; Kappelle, J.; ... ; Heart-Brain Connection Consortium 2021
Background Damping of heartbeat-induced pressure pulsations occurs in large arteries such as the aorta and extends to the small arteries and microcirculation. Since recently, 7 T MRI enables... Show moreBackground Damping of heartbeat-induced pressure pulsations occurs in large arteries such as the aorta and extends to the small arteries and microcirculation. Since recently, 7 T MRI enables investigation of damping in the small cerebral arteries. Purpose To investigate flow pulsatility damping between the first segment of the middle cerebral artery (M1) and the small perforating arteries using magnetic resonance imaging. Study Type Retrospective. Subjects Thirty-eight participants (45% female) aged above 50 without history of heart failure, carotid occlusive disease, or cognitive impairment. Field Strength/Sequence 3 T gradient echo (GE) T1-weighted images, spin-echo fluid-attenuated inversion recovery images, GE two-dimensional (2D) phase-contrast, and GE cine steady-state free precession images were acquired. At 7 T, T1-weighted images, GE quantitative-flow, and GE 2D phase-contrast images were acquired. Assessment Velocity pulsatilities of the M1 and perforating arteries in the basal ganglia (BG) and semi-oval center (CSO) were measured. We used the damping index between the M1 and perforating arteries as a damping indicator (velocity pulsatility(M1)/velocity pulsatility(CSO/BG)). Left ventricular stroke volume (LVSV), mean arterial pressure (MAP), pulse pressure (PP), and aortic pulse wave velocity (PWV) were correlated with velocity pulsatility in the M1 and in perforating arteries, and with the damping index of the CSO and BG. Statistical Tests Correlations of LVSV, MAP, PP, and PWV with velocity pulsatility in the M1 and small perforating arteries, and correlations with the damping indices were evaluated with linear regression analyses. Results PP and PWV were significantly positively correlated to M1 velocity pulsatility. PWV was significantly negatively correlated to CSO velocity pulsatility, and PP was unrelated to CSO velocity pulsatility (P = 0.28). PP and PWV were uncorrelated to BG velocity pulsatility (P = 0.25; P = 0.68). PWV and PP were significantly positively correlated with the CSO damping index. Data Conclusion Our study demonstrated a dynamic damping of velocity pulsatility between the M1 and small cerebral perforating arteries in relation to proximal stress. Level of Evidence 4 Technical Efficacy Stage 1 Show less
Mahdiui, M. el; Bijl, P. van der; Abou, R.; Lustosa, R.D.; Geest, R. van der; Marsan, N.A.; ... ; Bax, J.J. 2021
This study investigates the relation of non-invasive myocardial work and myocardial viability following ST-segment elevation myocardial infarction (STEMI) assessed on late gadolinium contrast... Show moreThis study investigates the relation of non-invasive myocardial work and myocardial viability following ST-segment elevation myocardial infarction (STEMI) assessed on late gadolinium contrast enhanced cardiac magnetic resonance (LGE CMR) and characterizes the remote zone using non-invasive myocardial work parameters. STEMI patients who underwent primary percutaneous coronary intervention (PCI) were included. Several non-invasive myocardial work parameters were derived from speckle tracking strain echocardiography and sphygmomanometric blood pressure, e.g.: myocardial work index (MWI), constructive work (CW), wasted work (WW) and myocardial work efficiency (MWE). LGE was quantified to determine infarct transmurality and scar burden. The core zone was defined as the segment with the largest extent of transmural LGE and the remote zone as the diametrically opposed segment without LGE. A total of 53 patients (89% male, mean age 58 +/- 9 years) and 689 segments were analyzed. The mean scar burden was 14 +/- 7% of the total LV mass, and 76 segments (11%) demonstrated transmural hyperenhancement, 280 (41%) non-transmural hyperenhancement and 333 (48%) no LGE. An inverse relation was observed between segmental MWI, CW and MWE and infarct transmurality (p < 0.05). MWI, CW and MWE were significantly lower in the core zone compared to the remote zone (p<0.05). In conclusion, non-invasive myocardial work parameters may serve as potential markers of segmental myocardial viability in post-STEMI patients who underwent primary PCI. Non-invasive myocardial work can also be utilized to characterize the remote zone, which is an emerging prognostic marker as well as a therapeutic target. (C) 2021 The Authors. Published by Elsevier Inc. Show less
Cardiac magnetic resonance (CMR) is emerging as an important tool in the assessment of heart failure with preserved ejection fraction (HFpEF). This study sought to investigate the prognostic value... Show moreCardiac magnetic resonance (CMR) is emerging as an important tool in the assessment of heart failure with preserved ejection fraction (HFpEF). This study sought to investigate the prognostic value of multiparametric CMR, including left and right heart volumetric assessment, native T1-mapping and LGE in HFpEF. In this retrospective study, we identified patients with HFpEF who have undergone CMR. CMR protocol included: cines, native T1-mapping and late gadolinium enhancement (LGE). The mean follow-up period was 3.2 +/- 2.4 years. We identified 86 patients with HFpEF who had CMR. Of the 86 patients (85% hypertensive; 61% males; 14% cardiac amyloidosis), 27 (31%) patients died during the follow up period. From all the CMR metrics, LV mass (area under curve [AUC] 0.66, SE 0.07, 95% CI 0.54-0.76, p = 0.02), LGE fibrosis (AUC 0.59, SE 0.15, 95% CI 0.41-0.75, p = 0.03) and native T1-values (AUC 0.76, SE 0.09, 95% CI 0.58-0.88, p < 0.01) were the strongest predictors of all-cause mortality. The optimum thresholds for these were: LV mass > 133.24 g (hazard ratio [HR] 1.58, 95% CI 1.1-2.2, p < 0.01); LGE-fibrosis > 34.86% (HR 1.77, 95% CI 1.1-2.8, p = 0.01) and native T1 > 1056.42 ms (HR 2.36, 95% CI 0.9-6.4, p = 0.07). In multivariate cox regression, CMR score model comprising these three variables independently predicted mortality in HFpEF when compared to NTproBNP (HR 4 vs HR 1.65). In non-amyloid HFpEF cases, only native T1 > 1056.42 ms demonstrated higher mortality (AUC 0.833, p < 0.01). In patients with HFpEF, multiparametric CMR aids prognostication. Our results show that left ventricular fibrosis and hypertrophy quantified by CMR are associated with all-cause mortality in patients with HFpEF. Show less
Hoekstra, M.; Ouweneel, A.B.; Price, J.; Geest, R. van der; Sluis, R.J. van der; Geerling, J.J.; ... ; Eck, M. van 2020
Scavenger receptor BI (SR-BI) has been suggested to modulate adipocyte function. To uncover the potential relevance of SR-BI for the development of obesity and associated metabolic complications,... Show moreScavenger receptor BI (SR-BI) has been suggested to modulate adipocyte function. To uncover the potential relevance of SR-BI for the development of obesity and associated metabolic complications, we compared the metabolic phenotype of wild-type and SR-BI deficient mice fed an obesogenic diet enriched in fat. Both male and female SR-BI knockout mice gained significantly more weight as compared to their wild-type counterparts in response to 12 weeks high fat diet feeding (1.5-fold; P < .01 for genotype). Plasma free cholesterol levels were ~2-fold higher (P < .001) in SR-BI knockout mice of both genders, whilst plasma cholesteryl ester and triglyceride concentrations were only significantly elevated in males. Strikingly, the exacerbated obesity in SR-BI knockout mice was paralleled by a better glucose handling. In contrast, only SR-BI knockout mice developed atherosclerotic lesions in the aortic root, with a higher predisposition in females. Biochemical and histological studies in male mice revealed that SR-BI deficiency was associated with a reduced hepatic steatosis degree as evident from the 29% lower (P < .05) liver triglyceride levels. Relative mRNA expression levels of the glucose uptake transporter GLUT4 were increased (+47%; P < .05), whilst expression levels of the metabolic PPARgamma target genes CD36, HSL, ADIPOQ and ATGL were reduced 39%-58% (P < .01) in the context of unchanged PPARgamma expression levels in SR-BI knockout gonadal white adipose tissue. In conclusion, we have shown that SR-BI deficiency is associated with a decrease in adipocyte PPARgamma activity and a concomitant uncoupling of obesity development from hepatic steatosis and glucose intolerance development in high fat diet-fed mice. Show less
Abou, R.; Prihadi, E.A.; Goedemans, L.; Geest, R. van der; Mahdiui, M. el; Schalij, M.J.; ... ; Delgado, V. 2020
Aims Left ventricular (LV) mechanical dispersion (MD) may result from heterogeneous electrical conduction and is associated with adverse events. The present study investigated (i) the association... Show moreAims Left ventricular (LV) mechanical dispersion (MD) may result from heterogeneous electrical conduction and is associated with adverse events. The present study investigated (i) the association between LV MD and the extent of LV scar as assessed with contrast-enhanced cardiac magnetic resonance (CMR) and (ii) the prognostic implications of LV MD in patients after ST-segment elevation myocardial infarction.Methods and results LV MD was calculated by echocardiography and myocardial scar was analysed on CMR data retrospectively. Infarct core and border zone were defined as >50% and 35-50% of maximal signal intensity, respectively. Patients were followed for the occurrence of the combined endpoint (all-cause mortality and appropriate implantable cardioverter-defibrillator therapy). In total, 96 patients (87% male, 57 +/- 10 years) were included. Median LV MD was 53.5 ms [interquartile range (IQR) 43.4-62.8]. On CMR, total scar burden was 11.4% (IQR 3.8-17.1%), infarct core tissue 6.2% (IQR 2.0-12.7%), and border zone was 3.5% (IQR 1.5-5.7%). Correlations were observed between LV MD and infarct core (r= 0.517, P < 0.001), total scar burden (r= 0.497, P < 0.001), and border zone (r=0.298, P=0.003). In total, 14 patients (15%) reached the combined endpoint. Patients with LV MD >53.5 ms showed higher event rates as compared to their counterparts. Finally, LV MD showed the highest area under the curve for the prediction of the combined endpoint.Conclusion LV MD is correlated with LV scar burden. In addition, patients with prolonged LV MD showed higher event rates. Finally, LV MD provided the highest predictive value for the combined endpoint when compared with other parameters. Show less
Muehlberg, F.; Stoetzner, A.; Forman, C.; Schmidt, M.; Riazy, L.; Dieringer, M.; ... ; Schulz-Menger, J. 2020
Purpose: Stress perfusion imaging plays a major role in non-invasive detection of coronary artery disease.We compared a compressed sensing-based and a conventional gradient echo perfusion sequence... Show morePurpose: Stress perfusion imaging plays a major role in non-invasive detection of coronary artery disease.We compared a compressed sensing-based and a conventional gradient echo perfusion sequence with regard to image quality and diagnostic performance.Method: Patients sent for coronary angiography due to pathologic stress perfusion CMR were recruited. All patients underwent two adenosine stress CMR using conventional TurboFLASH and prototype SPARSE sequence as well as quantitative coronary angiography with fractional flow reserve (FFR) within 6 weeks. Coronary angiography was considered gold standard with FFR < 0.75 or visual stenosis >90 % for identification of myocardial ischemia. Diagnostic performance of perfusion imaging was assessed in basal, mid-ventricular and apical slices by quantification of myocardial perfusion reserve (MPR) analysis utilizing the signal upslope method and a deconvolution technique using the fermi function model.Results: 23 patients with mean age of 69.6 +/- 8.9 years were enrolled. 46 % were female.Image quality was similar in conventional TurboFLASH sequence and SPARSE sequence (2.9 +/- 0.5 vs 3.1 +/- 0.7, p = 0,06). SPARSE sequence showed higher contrast-to-noise ratio (52.1 +/- 27.4 vs 40.5 +/- 17.6, p < 0.01) and signal-to-noise ratio (15.6 +/- 6.2 vs 13.2 +/- 4.2, p < 0.01) than TurboFLASH sequence. Dark-rim artifacts occurred less often with SPARSE (9 % of segments) than with TurboFLASH (23 %).In visual assessment of perfusion defects, SPARSE sequence detected less false-positive perfusion defects (n = 1) than TurboFLASH sequence (n = 3).Quantitative perfusion analysis on segment basis showed equal detection of perfusion defects for TurboFLASH and SPARSE with both upslope MPR analysis (TurboFLASH 0.88 +/- 0.18; SPARSE 0.77 +/- 0.26; p = 0.06) and fermi function model (TurboFLASH 0.85 +/- 0.24; SPARSE 0.76 +/- 0.30; p = 0.13).Conclusions: Compressed sensing perfusion imaging using SPARSE sequence allows reliable detection of myocardial ischemia. Show less
Background:There is an emerging body of evidence that supports the potential clinical value of left ventricular (LV) intracavity blood flow kinetic energy (KE) assessment using four-dimensional... Show moreBackground:There is an emerging body of evidence that supports the potential clinical value of left ventricular (LV) intracavity blood flow kinetic energy (KE) assessment using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR). The aim of this systematic review is to summarize studies evaluating LV intracavity blood flow KE quantification methods and its potential clinical significance.Methods:A systematic review search was carried out on Medline, Pubmed, EMBASE and CINAHL.Results:Of the 677 articles screened, 16 studies met eligibility. These included six (37%) studies on LV diastolic function, another six (37%) studies on heart failure or cardiomyopathies, three (19%) studies on ischemic heart disease or myocardial infarction and finally, one (6%) study on valvular heart disease, namely, mitral regurgitation. One of the main strengths identified by these studies is high reproducibility of LV blood flow KE hemodynamic assessment (mean coefficient of variability = 6 +/- 2%) for the evaluation of LV diastolic function.Conclusions:The evidence gathered in this systematic review suggests that LV blood flow KE has great promise for LV hemodynamic assessment. Studies showed increased diagnostic confidence at no cost of additional time. Results were highly reproducible with low intraobserver variability. Show less
Chronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid... Show moreChronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid levels. Here we determined, in a preclinical setting, whether the chronic presence of cholestatic liver disease also induces a concomitant negative impact on atherosclerosis susceptibility. Hereto, regular chow diet-fed atherosclerosis-susceptible hypercholesterolemic apolipoprotein E (APOE) knockout mice were treated with the bile duct toxicant alpha‑naphthylisothiocyanate (ANIT) for 8 weeks. ANIT exposure induced the development of fibrotic cholestatic liver disease as evident from collagen deposits and compensatory bile duct hyperproliferation within the liver and the rise in plasma levels of bilirubin (+60%; P<0.01) and bile acids (10-fold higher; P<0.01). Adrenal weights (+22%; P<0.01) and plasma corticosterone levels (+72%; P<0.01) were increased in ANIT-treated mice. In contrast, atherosclerosis susceptibility was not increased in response to ANIT feeding, despite the concomitant increase in plasma free cholesterol (+30%; P<0.01) and cholesteryl ester (+42%; P<0.001) levels. The ANIT-induced hypercorticosteronemia coincided with marked immunosuppression as judged from the 50% reduction (P<0.001) in circulating lymphocyte numbers. However, hepatic glucocorticoid signaling was not enhanced after ANIT treatment. It thus appears that the immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effect under cholestatic disease conditions. In conclusion, we have shown that cholestatic liver disease-associated endogenous glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE knockout mice. Our studies provide novel preclinical evidence for the observations that the hypercholesterolemia seen in cholestatic human subjects does not translate into a higher risk for atherosclerotic cardiovascular disease. Show less
Hoekstra, M.; Ouweneel, A.B.; Nahon, J.E.; Geest, R. van der; Kröner, M.J.; Sluis, R.J. van der; Eck, M. van 2019
ObjectiveSince cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie... Show moreObjectiveSince cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie glucocorticoid insufficiency in humans. In the current study, we specifically focused on the cholesterol efflux mediator ATP-binding cassette transporter G1 (ABCG1) as gene candidate.MethodsThe adrenal transcriptional response to fasting stress was measured in wild-type mice to identify putative novel gene candidates. Subsequently, the adrenal glucocorticoid function was compared between ABCG1 knockout mice and wild-type controls.ResultsOvernight food deprivation induced a change in relative mRNA expression levels of cholesterol metabolism-related proteins previously linked to steroidogenesis, i.e. scavenger receptor class B type I (+149%; P < 0.001), LDL receptor (−70%; P < 0.001) and apolipoprotein E (−41%; P < 0.01). Strikingly, ABCG1 transcript levels were also markedly decreased (−61%; P < 0.05). In contrast to our hypothesis that decreasing cholesterol efflux would increase the adrenal cholesterol pool and enhance glucocorticoid output, ABCG1 knockout mice as compared to wild-type mice exhibited a reduced ability to secrete corticosterone in response to an ACTH challenge (two-way ANOVA: P < 0.001 for genotype) or fasting stress. As a result, glucocorticoid target gene expression levels in liver and hypothalamus were reduced and blood lymphocyte concentrations and spleen weights increased in ABCG1 knockout mice under fasting stress conditions. This was paralleled by a 48% reduction in adrenal cholesteryl ester stores and stimulation of adrenal NPC intracellular cholesterol transporter 2 (+37%; P < 0.05) and apolipoprotein E (+59%; P < 0.01) mRNA expression.ConclusionABCG1 deficiency is associated with mild glucocorticoid insufficiency in mice. Show less
Kamphuis, V.P.; Westenberg, J.J.M.; Palen, R.L.F. van der; Blom, N.A.; Roos, A. de; Geest, R. van der; ... ; Roest, A.A.W. 2017
Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has... Show moreCholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18 ± 5 ng/ml vs 472 ± 58 ng/ml; P < 0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P < 0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P < 0.01) and 82% (P < 0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P < 0.05), which translated into a 73% lower plasma total cholesterol level (P < 0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia.In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. Show less
Venlet, J.; Kapel, G.F.L.; Piers, S.R.D.; Silva, M.D.; Geest, R. van der; Zeppenfeld, K. 2016
