Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Neonatal encephalopathy following hypoxia-ischemia (HI) is a leading cause of childhood death and morbidity. Hypothermia (HT), the only available but obligatory therapy is limited due to a short therapeutic window and limited efficacy. An adjuvant therapy overcoming limitations of HT is still missing. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promising therapeutic effects in various brain injury models. Challenges associated with MSCs' heterogeneity and senescence can be mitigated by the use of EVs from clonally expanded immortalized MSCs (ciMSCs). In the present study, we hypothesized that intranasal ciMSC-EV delivery overcomes limitations of HT. METHODS: Nine-day-old C57BL/6 mice were exposed to HI by occlusion of the right common carotid artery followed by 1 h hypoxia (10% oxygen). HT was initiated immediately after insult for 4 h. Control animals were kept at physiological body core temperatures. ciMSC-EVs or vehicle were administered intranasally 1, 3 and 5 days post HI/HT. Neuronal cell loss, inflammatory and regenerative responses were assessed via immunohistochemistry, western blot and real-time PCR 7 days after insult. Long-term neurodevelopmental outcome was evaluated by analyses of cognitive function, activity and anxiety-related behavior 5 weeks after HI/HT. RESULTS: In contrast to HT monotherapy, the additional intranasal therapy with ciMSC-EVs prevented HI-induced cognitive deficits, hyperactivity and alterations of anxiety-related behavior at adolescence. This was preceded by reduction of striatal neuronal loss, decreased endothelial, microglia and astrocyte activation; reduced expression of pro-inflammatory and increased expression of anti-inflammatory cytokines. Furthermore, the combination of HT with intranasal ciMSC-EV delivery promoted regenerative and neurodevelopmental processes, including endothelial proliferation, neurotrophic growth factor expression and oligodendrocyte maturation, which were not altered by HT monotherapy. CONCLUSION: Intranasal delivery of ciMSC-EVs represents a novel adjunct therapy, overcoming limitations of acute HT thereby offering new possibilities for improving long-term outcomes in neonates with HI-induced brain injury.

Impact of statins based on high-risk plaque features on coronary plaque progression in mild stenosis lesions: results from the PARADIGM study.

AIMS: To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA). METHODS AND RESULTS: We analyzed mild stenosis (25-49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02-3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09-2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07-2.22; P = 0.020). CONCLUSION: In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02803411.

Glycemic control is independently associated with rapid progression of coronary atherosclerosis in the absence of a baseline coronary plaque burden: a retrospective case-control study from the PARADIGM registry.

BACKGROUND: The baseline coronary plaque burden is the most important factor for rapid plaque progression (RPP) in the coronary artery. However, data on the independent predictors of RPP in the absence of a baseline coronary plaque burden are limited. Thus, this study aimed to investigate the predictors for RPP in patients without coronary plaques on baseline coronary computed tomography angiography (CCTA) images. METHODS: A total of 402 patients (mean age: 57.6 ± 10.0 years, 49.3% men) without coronary plaques at baseline who underwent serial coronary CCTA were identified from the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry and included in this retrospective study. RPP was defined as an annual change of ≥ 1.0%/year in the percentage atheroma volume (PAV). RESULTS: During a median inter-scan period of 3.6 years (interquartile range: 2.7-5.0 years), newly developed coronary plaques and RPP were observed in 35.6% and 4.2% of the patients, respectively. The baseline traditional risk factors, i.e., advanced age (≥ 60 years), male sex, hypertension, diabetes mellitus, hyperlipidemia, obesity, and current smoking status, were not significantly associated with the risk of RPP. Multivariate linear regression analysis showed that the serum hemoglobin A1c level (per 1% increase) measured at follow-up CCTA was independently associated with the annual change in the PAV (ß: 0.098, 95% confidence interval [CI]: 0.048-0.149; P < 0.001). The multiple logistic regression models showed that the serum hemoglobin A1c level had an independent and positive association with the risk of RPP. The optimal predictive cut-off value of the hemoglobin A1c level for RPP was 7.05% (sensitivity: 80.0%, specificity: 86.7%; area under curve: 0.816 [95% CI: 0.574-0.999]; P = 0.017). CONCLUSION: In this retrospective case-control study, the glycemic control status was strongly associated with the risk of RPP in patients without a baseline coronary plaque burden. This suggests that regular monitoring of the glycemic control status might be helpful for preventing the rapid progression of coronary atherosclerosis irrespective of the baseline risk factors. Further randomized investigations are necessary to confirm the results of our study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02803411.

Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model.

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy.

Glioma: molecular signature and crossroads with tumor microenvironment.

In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas' grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.

Radiation Dose and Image Quality of a High-Pitch Prospective Spiral First Approach in Coronary Computed Tomography Angiography (CCTA).

Objective: To investigate a high-pitch spiral first (HPSF) approach for coronary computed tomography angiography (CCTA) in an unselected patient cohort and compare diagnostic yield and radiation exposure to CCTAs acquired via conventional, non-high-pitch spiral first (NHPSF) scan regimes. Materials and Methods: All consecutive patients from 1 January 2015 to 31 December 2017 were included. Two investigation protocols (HPSF/NHPSF) were used with the aim to achieve diagnostic image quality of all coronary segments. Low-pitch secondary scans followed the initial examination if image quality was unsatisfactory. Dosage and image quality were compared between both regimes. Results: 1410 patients were subject to a HPSF and 236 patients to a NHPSF approach. While the HPSF approach led to a higher fraction of re-scans (35% vs. 11%, p < 0.001), the fraction of aggregate scans that remained non-diagnostic after considering the initial and secondary scan was comparably low for the HPSF and NHPSF approach (0.78 vs. 0%, p = 0.18). Aggregate radiation exposure in the HPSF protocol was significantly lower (1.12 mSv (IQR: 0.73, 2.10) vs. 3.96 mSv (IQR: 2.23, 8.33) p < 0.001). Conclusions: In spite of a higher number of re-scans, a HPSF approach leads to a reduction in overall radiation exposure with diagnostic yields similar to a NHPSF approach.

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. OBJECTIVES: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. METHODS: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. RESULTS: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. CONCLUSIONS: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Association between Aortic Valve Calcification Progression and Coronary Atherosclerotic Plaque Volume Progression in the PARADIGM Registry.

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm3 ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized ß = 0.24; 95% CI: 0.16, 0.32; P < .001) and both calcified (ß = 0.26; 95% CI: 0.18, 0.34; P < .001) and noncalcified (ß = 0.17; 95% CI: 0.08, 0.25; P < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (ß = 0.13; 95% CI: 0.03, 0.22; P = .01), driven solely by calcified plaque volume (ß = 0.24; 95% CI: 0.14, 0.34; P < .001) but not noncalcified plaque volumes (ß = -0.06; 95% CI: -0.14, 0.03; P = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.

Rodent Models to Analyze the Glioma Microenvironment.

Animal models are still indispensable for understanding the basic principles of glioma development and invasion. Preclinical approaches aim to analyze the treatment efficacy of new drugs before translation into clinical trials is possible. Various animal disease models are available, but not every approach is useful for addressing specific questions. In recent years, it has become increasingly evident that the tumor microenvironment plays a key role in the nature of glioma. In addition to providing an overview, this review evaluates available rodent models in terms of usability for research on the glioma microenvironment.

Neurobehavioral effects in rats with experimentally induced glioblastoma after treatment with the mTOR-inhibitor rapamycin.

Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidities are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)- signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM animals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplantation medicine, immunotherapy, and oncology.

An unusual case of severe myocarditis in a genetic cardiomyopathy: a case report.

BACKGROUND: Myocarditis is an inflammatory disease of the myocardium caused by infectious pathogens, immune-mediated conditions, or toxic agents. This report explores a rare case of severe myocarditis occurring in an inherited cardiomyopathy. CASE SUMMARY: A 24-year-old female patient presented with progressing dyspnoea and chest discomfort. Echocardiography and cardiac magnetic resonance imaging revealed dilated cardiomyopathy (DCM) with severe biventricular dysfunction [left ventricle ejection fraction (LV-EF) 10%]. Myocardial inflammation was suspected due to extensive subendocardial to transmural late gadolinium enhancement. Endomyocardial biopsy (EMB) showed severe chronic lymphocytic myocarditis. As inflammatory DCM was assumed, immunosuppressive therapy with prednisolone was initiated in addition to standard heart failure therapy. Endomyocardial biopsy after 3 months showed resolving inflammation. However, a marked architectural disarray observed in all biopsies raised the suspicion of an inherited cardiomyopathy. Genetic testing revealed a de novo mutation with effect on splicing of lysosome-associated membrane protein 2, as found in Danon disease. Periodic acid-Schiff (PAS) staining confirmed a glycogen storage disorder. Immunosuppressive therapy was intensified due to reactivation of myocardial inflammation and led to improvement of LV-EF and to significant symptom relief over a 16-month follow-up period. DISCUSSION: This is the first report of Danon disease initially presenting as a severe myocarditis. It illustrates the clinical value of EMB for diagnosis and immunosuppressive therapy monitoring in chronic myocarditis. Increasing evidence suggests that myocardial inflammation may modify disease progression and prognosis in inherited cardiomyopathies. The causal role of cardiac protein mutations in the pathophysiology of myocarditis remains to be determined.

Association of High-Density Calcified 1K Plaque With Risk of Acute Coronary Syndrome.

Importance: Plaque morphologic measures on coronary computed tomography angiography (CCTA) have been associated with future acute coronary syndrome (ACS). However, the evolution of calcified coronary plaques by noninvasive imaging is not known. Objective: To ascertain whether the increasing density in calcified coronary plaque is associated with risk for ACS. Design, Setting, and Participants: This multicenter case-control cohort study included individuals enrolled in ICONIC (Incident Coronary Syndromes Identified by Computed Tomography), a nested case-control study of patients drawn from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry, which included 13 study sites in 8 countries. Patients who experienced core laboratory-verified ACS after baseline CCTA (n = 189) and control individuals who did not experience ACS after baseline CCTA (n = 189) were included. Patients and controls were matched 1:1 by propensity scores for age; male sex; presence of hypertension, hyperlipidemia, and diabetes; family history of premature coronary artery disease (CAD); current smoking status; and CAD severity. Data were analyzed from November 2018 to March 2019. Exposures: Whole-heart atherosclerotic plaque volume was quantitated from all coronary vessels and their branches. For patients who underwent invasive angiography at the time of ACS, culprit lesions were coregistered to baseline CCTA lesions by a blinded independent reader. Low-density plaque was defined as having less than 130 Hounsfield units (HU); calcified plaque, as having more than 350 HU and subcategorized on a voxel-level basis into 3 strata: 351 to 700 HU, 701 to 1000 HU, and more than 1000 HU (termed 1K plaque). Main Outcomes and Measures: Association between calcium density and future ACS risk. Results: A total of 189 patients and 189 matched controls (mean [SD] age of 59.9 [9.8] years; 247 [65.3%] were male) were included in the analysis and were monitored during a mean (SD) follow-up period of 3.9 (2.5) years. The overall mean (SD) calcified plaque volume (>350 HU) was similar between patients and controls (76.4 [101.6] mm3 vs 99.0 [156.1] mm3; P = .32), but patients who experienced ACS exhibited less 1K plaque (>1000 HU) compared with controls (3.9 [8.3] mm3 vs 9.4 [23.2] mm3; P = .02). Individuals within the highest quartile of 1K plaque exhibited less low-density plaque, as a percentage of total plaque, when compared with patients within the lower 3 quartiles (12.6% [10.4%] vs 24.9% [20.6%]; P < .001). For 93 culprit precursor lesions detected by CCTA, the volume of 1K plaque was lower compared with the maximally stenotic lesion in controls (2.6 [7.2] mm3 vs 7.6 [20.3] mm3; P = .01). The per-patient and per-lesion results were similar between the 2 groups when restricted to myocardial infarction cases. Conclusions and Relevance: Results of this study suggest that, on a per-patient and per-lesion basis, 1K plaque was associated with a lower risk for future ACS and that measurement of 1K plaque may improve risk stratification beyond plaque burden.

Application of Low Tube Potentials in CCTA: Results From the PROTECTION VI Study.

OBJECTIVES: The aim of this study was to assess the use of low tube potentials for coronary computed tomography angiography (CCTA) in worldwide clinical practice and its influence on radiation exposure, contrast agent volume, and image quality. BACKGROUND: CCTA is frequently used in clinical practice. Lowering of tube potential is a potent method to reduce radiation exposure and to economize contrast agent volume. METHODS: CCTAs of 4,006 patients from 61 international study sites were analyzed regarding very-low (≤80 kVp), low (90 to 100 kVp), conventional (110 to 120 kVp), and high (≥130 kVp) tube potentials. The impact on dose-length product (DLP) and contrast agent volume was analyzed. Image quality was determined by evaluation of the diagnostic applicability and assessment of the objective image parameters signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR). RESULTS: When compared with conventional tube potentials, low tube potentials were used in 56% of CCTAs (≤80 kVp: 9%; 90 to 100 kVp: 47%), which varied among sites from 0% to 100%. Tube potential reduction was associated with low-cardiovascular risk profile, low body mass index (BMI), and new-generation scanners. Median radiation exposure was lowered by 68% or 50% and median contrast agent volume by 25% or 13% for tube potential protocols of ≤80 kVp or 90 to 100 kVp when compared with conventional tube potentials, respectively (all p < 0.001). With the use of lower tube potentials, the frequency of diagnostic scans was maintained (p = 0.41), whereas SNR and CNR significantly improved (both p < 0.001). Considering BMI eligibility criteria, 58% (n = 946) of conventionally scanned patients would have been suitable for low tube potential protocols, and 44% (n = 831) of patients scanned with 90 to 100 kVp would have been eligible for very-low tube potential CCTA imaging of ≤80 kVp. CONCLUSIONS: This large international registry confirms the feasibility of tube potential reduction in clinical practice leading to lower radiation exposure and lower contrast volumes. The current registry also demonstrates that this strategy is still underused in daily practice. (PROspective multicenter registry on radiaTion dose Estimates of cardiac CT angIOgraphy iN daily practice in 2017 [PROTECTION-VI]; NCT02996903).

Impact of optic canal decompression on visual outcome in subtotal resected skull base meningiomas.

BACKGROUND: Visual impairment (VI) due to neoplastic infiltration of the optic canal (OC) is frequently seen in skull base meningiomas representing a significant restriction in patients` quality of life. However, the delicate anatomy of this region often prevents gross total tumor resection. The aim of the present study was to evaluate the impact of intradural OC decompression and postoperative oncological procedure on preservation of visual acuity in subtotal resected skull base meningiomas. METHODS: A retrospective analysis of 31 consecutive patients (19 females, 12 males; mean age 53 [range 18-78]), treated in our institution between 01/2011- 09/2014 was performed. Patients` charts were analyzed with special respect to operative procedure, postoperative treatment and procedural impact on late visual function. RESULTS: Most patients (74.2%) had VI prior to surgery. A pterional craniotomy (97%) facilitated subtotal tumor removal in 71% of the patients with no intraoperative and a low rate (6.4%) of postoperative complications. Adjunctive radiotherapy was performed in 19.3% of the patients. Preoperative visual acuity was preserved or improved in 92% of the patients. Substantial tumor regrowth occurred in only 11.2% of the patients. CONCLUSIONS: Intradural decompression of the OC stabilizes visual function in subtotally resected skull base meningiomas. Moreover, adjuvant radiotherapy seems to further benefit visual outcome which has to be evaluated in further prospective studies.

Smoking and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients: a substudy from the randomized TROPICAL-ACS trial.

AIMS: Prior analyses disclosed variations in antiplatelet drug response and clinical outcomes between smokers and non-smokers, thus the safety and efficacy of any dual antiplatelet therapy (DAPT) de-escalation strategy may differ in relation to smoking status. Hence, we assessed the impact of smoking on clinical outcomes and adenosine diphosphate-induced platelet aggregation following guided de-escalation of DAPT in invasively managed acute coronary syndrome (ACS) patients. METHODS AND RESULTS: The multicentre TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to standard treatment with prasugrel for 12 months (control group) or a platelet function testing guided de-escalation of DAPT. Current smokers (n = 1182) showed comparable event rates between study groups [6.6% vs. 6.6%; hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.64-1.56, P > 0.99]. In non-smokers (n = 1428), a guided DAPT de-escalation was associated with a lower 1-year incidence of the primary endpoint [cardiovascular death, myocardial infarction, stroke, or bleeding ≥ Grade 2 according to Bleeding Academic Research Consortium (BARC) criteria] compared with control group patients (7.9% vs. 11.0%; HR 0.71, 95% CI 0.50-0.99, P = 0.048). This reduction was mainly driven by a lower rate of BARC ≥ Grade 2 bleedings (5.2% vs. 7.7%; HR 0.68, 95% CI 0.45-1.03, P = 0.066). There was no significant interaction of smoking status with treatment effects of guided DAPT de-escalation (Pint = 0.23). Adenosine diphosphate-induced platelet aggregation values were higher in current smokers [median 28 U, interquartile range (IQR: 20-40)] vs. non-smoker [median 24 U (16-25), P < 0.0001] in the control group and in current smokers [median 42 U, IQR (27-68)] vs. non-smoker [median 37 U, IQR (25-55), P < 0.001] in the monitoring group. CONCLUSION: Guided DAPT de-escalation appears to be equally safe and effective in smokers and non-smokers. Regardless of smoking status and especially for those patients deemed unsuitable for 1 year of potent platelet inhibition this DAPT strategy might be used as an alternative antiplatelet treatment regimen.

Point of Care Clinical Risk Score to Improve the Negative Diagnostic Utility of an Agatston Score of Zero: Averting the Need for Coronary Computed Tomography Angiography.

BACKGROUND: Coronary artery calcification is a marker of underlying atherosclerotic vascular disease. The absence of coronary artery calcification is associated with a low prevalence of obstructive coronary artery disease (CAD), but it cannot be ruled out completely. We sought to develop a clinical tool that can be added to Agatston score of zero to rule out obstructive CAD with high accuracy. METHODS: We developed a clinical score retrospectively from a cohort of 4903 consecutive patients with an Agatston score of zero. Patients with prior diagnosis of CAD, coronary percutaneous coronary intervention, or surgical revascularization were excluded. Obstructive CAD was defined as any epicardial vessel diameter narrowing of ≥50%. The score was validated using an external cohort of 4290 patients with an Agatston score of zero from a multinational registry. RESULTS: The score consisted of 7 variables: age, sex, typical chest pain, dyslipidemia, hypertension, family history, and diabetes mellitus. The model was robust with an area under the curve of 0.70 (95% CI, 0.65-0.76) in the derivation cohort and 0.69 (95% CI, 0.65-0.72) in the validation cohort. Patients were divided into 3 risk groups based on the score: low (≤6), intermediate (7-13), and high (≥14). Patients who score ≤6 have a negative likelihood ratio of 0.42 for obstructive CAD, whereas those who score ≥14 have a positive likelihood ratio of >5.5 for obstructive CAD. The outcome was ruled out in >98% of patients with a score ≤6 in the validation cohort. CONCLUSIONS: We developed a score that may be used to identify the likelihood of obstructive CAD in patients with an Agatston score of zero, which may be used to direct the need for additional testing. However, the results of this retrospective analysis are hypothesis generating and before clinical implementation should be validated in a trial with a prospectively collected data.

Behavioral conditioning of anti-proliferative and immunosuppressive properties of the mTOR inhibitor rapamycin.

Suppression of immune functions can be elicited by behavioral conditioning using drugs such as cyclosporine A, cyclophosphamide, or opioids. Nevertheless, little is known regarding the conditioned actions of clinically approved immunosuppressive drugs with distinct cell signaling pathways. The present study tested the assumption to condition immunopharmacological properties of rapamycin (sirolimus), a small-molecule drug widely used as anti-tumor medication and to prevent graft rejection. For this purpose, a conditioned taste avoidance (CTA) paradigm was used, pairing the presentation of a novel taste (saccharin) as conditioned stimulus (CS) with injections of rapamycin as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time revealed that conditioning with rapamycin induced an only moderate CTA. However, pronounced conditioned immunopharmacological effects were observed, reflected by significantly reduced levels of IL-10 cytokine production and diminished proliferation of splenic CD4+ and CD8+ T cells in Dark Agouti and Fischer 344 rats. For one, these findings support earlier observations revealing that not a pronounced CTA but rather re-exposure to the CS or taste itself is essential for conditioned immunosuppression. Moreover, our results provide first evidence that the phenomenon of learned immune responses generalizes across many, if not all, small-molecule drugs with immunosuppressive properties, thereby providing the basis for employing learned immunopharmacological strategies in clinical contexts such as supportive therapy.

Exclusion of left atrial thrombus by dual-source cardiac computed tomography prior to catheter ablation for atrial fibrillation.

OBJECTIVES: Thromboembolic complications during atrial fibrillation (AF) ablation due to mobilisation of a pre-existing thrombus formation (TF) in the left atrium (LA) are devastating. The gold standard to exclude LA TF is transesophageal echocardiography (TEE). The present study compares sensitivity and specificity of a dual-source cardiac-computed tomography (DS-CT) with TEE for TF exclusion prior to AF ablation. In addition, CT protocols with and without ECG synchronized were evaluated. METHODS: In 622 patients, DS-CT as well as TEE to exclude TF was performed less than 48 h prior to AF ablation. Mean age of patients was 60 ± 10 years (69% males, 61% paroxysmal AF). During DS-CT, 280 patients (45%) were in AF. An ECG-synchronized DS-CT was performed in 332 patients, whereas 290 patients underwent DS-CT without ECG synchronization. RESULTS: In all patients without suspected TF on DS-CT (n = 552; 88.7%), no thrombus was found on TEE. A TF was suspected on DS-CT in 70 patients, of whom only three patients showed TF on TEE. No TF was detected in the other 67 patients (Fig. 1). Overall, sensitivity for TF detection in DS-CT was 100% and specificity was 89.2% (positive predictive value 4.3%, negative predictive value 100%). The CT protocol (ECG-synchronized versus non-ECG-synchronized) had no significant influence on diagnostic accuracy. Mean dose length product during DS CT was 282 ± 287 mGy cm (synchronized) versus 136 ± 55 mGy cm (non-synchronized) with p < 0.0001. CONCLUSIONS: DS-CT is a highly sensitive method for LA thrombus detection in patients undergoing AF ablation. It delivers additional anatomic details of pulmonary veins and LA anatomy with an acceptable radiation exposure. Non-ECG-synchronized DS-CT showed a significantly lower radiation exposure, whereas diagnostic accuracy was comparable. Therefore, DS-CT might serve as primary method to exclude LA TF in patients undergoing AF ablation.

Impact of diabetes on coronary artery plaque volume by coronary CT angiography and subsequent adverse cardiac events.

BACKGROUND: To investigate the impact of diabetes on coronary artery total plaque volume (TPV) and adverse events in long-term follow-up. METHODS: One-hundred-and-eight diabetic patients were matched to 324 non-diabetic patients, with respect to age, sex, body-mass index, hypertension, smoking habits, LDL and HDL cholesterol, family history for CAD as well as aspirin and statin medication. In all patients, TPV was quantified from coronary CT angiographies (CTA) using dedicated software. All-cause mortality, acute coronary syndrome and late revascularisation (>90 days) served as combined endpoint. RESULTS: Patients were followed for 5.6 years. The endpoint occurred in 18 (16.7%) diabetic and 26 (8.0%) non-diabetic patients (odds ratio 2.3, p = 0.03). Diabetic patients had significantly higher TPV than non-diabetic patients (55.1 mm³ [IQR: 6.2 and 220.4 mm³] vs. 24.9 mm³ [IQR: 0 and 166.7 mm³], p = 0.02). A TPV threshold of 110.5 mm³ provided good separation of diabetic and non-diabetic patients at higher and lower risk for adverse events. Noteworthy, diabetic and non-diabetic patients with a TPV<110.5 mm³ had comparable outcome (hazard ratio: 1.3, p = 0.59), while diabetic patients with TPV>110.5 mm³ had significantly higher incidence of adverse events (hazard ratio 2.3, p = 0.03) compared to non-diabetic patients with TPV>110.5 mm³. There was incremental prognostic value in diabetic and non-diabetic patients over the Framingham Risk Score (Integrated Discrimination Improvement: 0.052 and 0.012, p for both <0.05). CONCLUSION: Diabetes is associated with significantly higher TPV, which is independent of other CAD risk factors. Quantification of TPV improves the identification of diabetic patients at higher risk for future adverse events.