Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study.

Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

Impact of preoperative haemoglobin A1c levels on postoperative outcomes in adults undergoing major noncardiac surgery: A systematic review.

AIMS: Diabetes is known to increase morbidity and mortality after major surgery. However, literature is conflicting on whether elevated preoperative haemoglobin A1c (HbA1c) levels are associated with worse outcomes following major noncardiac surgery. We aimed to investigate the effect of incremental preoperative HbA1c levels on postoperative outcomes in adults who had undergone major noncardiac surgery. METHODS: We systematically searched PubMed, EMBASE and the Cochrane Library databases for eligible studies published between January 2012 and July 2023. Randomised controlled trials and observational studies (cohort and case-control studies) which measured HbA1c within 6 months before surgery and compared outcomes between at least three incremental subgroups or analysed HbA1c as a continuous variable were included. The systematic review protocol was registered with PROSPERO (CRD42023391946). RESULTS: Twenty observational studies investigating outcomes across multiple surgical types were included. Higher preoperative HbA1c levels were associated with increased odds of overall postoperative complications, postoperative acute kidney injury, anastomotic leak, surgical site infections and increased length of stay. Each 1% increase in preoperative HbA1c was associated with increased odds of these complications. No association with reoperations and 30-day mortality was identified. The literature was highly variable with respect to composite major complications, perioperative cardiovascular events, hospital readmissions, postoperative pneumonia and systemic thromboembolism. CONCLUSIONS: Current evidence suggested that higher preoperative HbA1c levels were associated with increased odds of postoperative complications and extended length of stay in adults undergoing major noncardiac surgery. Further high-quality studies would be needed to quantify the risks posed and determine whether early intervention improves outcomes.

A retrospective review of the short Synacthen test in Queensland hospitals.

BACKGROUND: The short Synacthen test (SST) is widely used to investigate adrenal insufficiency, but it can be time-consuming, costly and labour-intensive to perform and is not without risk of adverse events. AIM: To review SST requesting patterns and practices across public hospitals in Queensland. METHODS: The electronic medical records of patients who underwent a SST with Pathology Queensland between January 2020 and December 2020 were reviewed to collect data regarding the indication for the test, the requesting speciality, SST results and any adverse events. RESULTS: Six hundred and fifty-two SSTs were identified, of which 363 individual patients were included in the analysis. The majority of the tests (n = 198, 54.5%) were performed in the inpatient setting. Endocrinology most commonly ordered SSTs (n = 188, 51.8%). The suspected aetiology of adrenal insufficiency was unclear in a large proportion of requests (n = 167, 46.0%). Static testing of morning cortisol prior to SST was performed in only 249 (68.6%) patients. Of 140 inpatients data, 17.9% (n = 25) showed a robust static cortisol of ≥400 nmol/L and were treated as having normal adrenal function, suggesting SST was unnecessary in these patients. Twenty-two (6.1%) patients had a documented adverse event occurring during or after the SST. CONCLUSIONS: There was wide variability in requesting patterns and practices for SSTs across Queensland. More than one in six SSTs could have been avoided if a static morning cortisol had been performed prior. Clinician education and the adoption of a structured referral form may improve testing practices.

Inclusion of Social Work in Comprehensive Palliative Care to Address Psychosocial Needs of Advanced Cancer Patients in Vietnam.

The need for psychosocial care among patients with serious illnesses and available social work services continues to be great, especially in low- and middle-income countries. To evaluate the specific needs of Vietnamese cancer patients' quality of life (QOL), prevalence and severity of symptoms including depression and anxiety, and caregiver burden were assessed. Data on QOL, mood, caregiver burden, and other parameters were collected through face-to-face and phone- interviews. The QOL assessed by European Quality of Life scale version 5D (EQ5D) was poor but consistent with other studies of cancer patients. Assessed by the Hospital Anxiety and depression Scale (HADS), borderline or severe anxiety and depression were prevalent. Caregiver burden was high for one third of study participants. These results confirm the need among cancer patients for psycho-social support services that currently are rarely available in Vietnam. In light of this need, a comprehensive palliative care (CPC) service, including social work, was created to improve the quality of life (QOL) of Vietnamese cancer patients.

Psidium guajava L.- dichloromethane and ethyl acetate fractions ameliorate striped catfish (Pangasianodon hypophthalmus) status via immune response, inflammatory, and apoptosis pathways.

Psidium guajava L. is known to possess immune-modulatory properties in humans and other mammals. Although the positive effects of P. guajava-based diets on the immunological status have been shown for some fish species, the underlying molecular mechanisms of its protective effects remain to be investigated. The aims of this study were to evaluate the immune-modulatory effects of two guava fractions from dichloromethane (CC) and ethyl acetate (EA) on striped catfish with in vitro and in vivo experiments. Striped catfish head kidney leukocytes were stimulated with 40, 20, 10 and 0 µg/ml of each extract fraction, and the immune parameters (ROS, NOS, and lysozyme) were examined at 6 and 24 h post stimulation. A final concentration of each fraction at 40, 10 and 0 µg/fish was then intraperitoneally injected into the fish. After 6, 24, and 72 h of administration, immune parameters as well as the expression of some cytokines related to innate and adaptive immune responses, inflammation, and apoptosis were measured in the head kidney. Results indicated that the humoral (lysozyme) and cellular (ROS and NOS) immune endpoints were regulated differently by CC and EA fractions depending on dose and time in both, in vitro and in vivo experiments. With regards to the in vivo experiment, the CC fraction of the guava extract could significantly enhance the TLRs-MyD88-NF-κB signaling pathway by upregulating its cytokine genes (tlr1, tlr4, myd88, and traf6), following the upregulation of inflammatory (nfκb, tnf, il1ß, and il6) and apoptosis (tp53 and casp8) genes 6 h after injection. Moreover, fish treated with both CC and EA fractions significantly enhanced cytokine gene expression including lys and inos at the later time points - 24 h or 72 h. Our observations suggest that P. guajava fractions modulate the immune, inflammatory, and apoptotic pathways.

Peripheral access size evaluation in transfemoral transcatheter aortic valve replacement.

BACKGROUND/AIM: Peripheral access vessel dimensions in the general patient population screened for transcatheter aortic valve replacement (TAVR) can offer insight into the indications for pre-TAVR computed tomography angiography (CTA) assessment. We seek to determine peripheral access vessel sizes in patients screened for TAVR and association with patient characteristics. MATERIALS AND METHODS: All patients with severe, symptomatic aortic stenosis screened for TAVR at a high-volume center from April 2012 to March 2019 were retrospectively reviewed. For each patient, contrast-enhanced CTA was used to determine the minimal luminal diameters (MLDs) of the transfemoral access vessels, as measured between the inguinal ligament and the deep femoral artery for the femoral artery, and proximal to the inguinal ligament for the external and common iliac arteries, respectively. Paired and independent samples t-tests were used to compare means and regression analyses were performed to determine factors associated with MLD. RESULTS: A total of 1049 screened patients were included of which 826 (78.7%) underwent TAVR and 551 (52.5%) were male. The mean age was 80.6 (±9.6) years and the mean body mass index (BMI) was 26.7 (±5.9) kg/m2 . About 152 (14.5%) had peripheral vascular disease and 153 (14.6%) had chronic kidney disease. The mean (±2 standard deviations) MLDs of the right and left femoral arteries were 7.73 mm (4.68-10.78) and 7.68 mm (4.63-10.72), respectively. Male sex and BMI were associated with larger average femoral MLD while hyperlipidemia, hypertension, smoking, peripheral vascular disease, and coronary artery disease were inversely associated. CONCLUSION: Most patients screened for TAVR have minimum peripheral access vessel sizes exceeding the recommended minimum access route diameters of modern transcatheter heart valves. As sheath sizes decrease, clinicians must carefully judge patient individual risk factors to determine whether a pre-TAVR CTA assessing peripheral access vessel dimensions and anatomical contraindications is indicated. Larger studies and randomized controlled trials are required to compare the outcomes of TAVR with and without preoperative CTA.

Combination Biomarkers for Risk Stratification in Patients With Chronic Heart Failure Biomarkers Prognostication in HF.

BACKGROUND: Current guidelines recommend measuring natriuretic peptide biomarkers to establish prognosis in patients with chronic heart failure with reduced ejection fraction (HFrEF). We assessed whether a combination biomarkers approach improve prognostication in patients with stable HFrEF. METHODS AND RESULTS: An observational cohort study recruited 202 patients with stable HFrEF at a single center, tertiary care hospital undergoing elective cardiac resynchronization therapy device placement from 2013 to 2015. Twenty-four biomarkers were analyzed individually and in combination using Cox proportion hazard regression model for major adverse cardiac events (ie, death, cardiac transplant, left ventricular assist device placement), and major adverse cardiac events plus HF hospitalizations. The single best biomarker for predicting major adverse cardiac events is peripheral mid-regional pro-adrenomedullin (C statistic = 0.771 ± 0.045) compared to current guideline recommended N-terminal pro b-type natriuretic peptide (C=0.668 ± 0.046). The best combined biomarkers for predicting major adverse cardiac events are blood urea nitrogen, coronary sinus C-reactive protein, peripheral mid-regional pro-atrial natriuretic peptide and peripheral soluble IL-1 receptor-like 1 (C = 0.767 ± 0.036). CONCLUSIONS: In this observational cohort, the combined biomarkers (blood urea nitrogen, C-reactive protein, mid-regional pro-atrial natriuretic peptide and soluble IL-1 receptor-like 1) or the single biomarker (mid-regional pro-adrenomedullin) was superior to N-terminal pro B-type natriuretic peptide, the current guideline recommended biomarker in predicting cardiovascular outcomes in patients with HFrEF. Larger studies are needed to validate these findings and examine whether single or combined biomarkers improve HFrEF prognostication.

Immunomodulatory potential of extracts, fractions and pure compounds from Phyllanthus amarus and Psidium guajava on striped catfish (Pangasianodon hypophthalmus) head kidney leukocytes.

This study aimed to identify major phytochemical constituents, as well as compare the immunomodulatory effects of Psidium guajava L. and Phyllanthus amarus Schun and Thonn crude ethanol extracts and their fractions on striped catfish (Pangasianodon hypophthalmus) head kidney leukocytes (HKLs). Moreover, pure constituents were also investigated for their effects on those cells: hypophyllanthin, identified as a major constituent of P. amarus crude extracts and its hexane fraction; corosolic acid, ursolic acid, and oleanolic acid, identified in P. guajava crude extract, ethyl acetate and dichloromethane fractions; with other terpenic derivatives, as well as guajaverin and avicularin, identified with other flavonoids by LC-UV-MS in the crude P. guajava extract and its ethyl acetate fraction. Cell viability, respiratory burst assay (RBA), nitric oxide synthase (NOS) and lysozyme activity in HKLs were analyzed after 24 h stimulation with each extract (10, 20 and 40 µg/mL) or pure compound (7.5, 15 and 30 µM). Our results show that the hexane fraction of both plant extracts inhibited the viability of HKLs, while several other fractions enhanced the cell viability. All P. guajava fractions at all or some concentration considerably enhanced the RBA production in HKLs. Similarly, NOS production was also significantly increased by some or all concentrations of P. guajava dichloromethane and ethyl acetate fractions. However, the NOS production was dose-dependently inhibited in HKLs treated with Pa ethyl acetate and both plants aqueous fractions at 10 or 10 and 40 µg/mL respectively. The lysozyme activity in cells treated with P. guajava crude extracts and all its organic solvent fractions were stronger than those in P. amarus treatments. Pure compounds including corosolic acid, guajaverin, ursolic acid, hypophyllanthin inhibited the HKLs viability according to concentration and type of compound. All pure compounds except avicularin significantly stimulated, at certain or all concentrations, the RBA production and/or the lysozyme activity in HKLs. The NOS production was significantly reduced in HKLs treated with oleanolic acid (30 µM) and hypophyllanthin (7.5 µM) while its level was increased by hypophyllanthin at 30 µM. These results highlighted that the crude ethanol extracts of P. guajava and P. amarus, their fractions and some of their pure components at certain concentrations can potentially act as immunomodulators, and could be considered as valuable candidates in fishery sciences.

Left ventricular wall thickness assessed by cardiac computed tomography and cardiac resynchronization therapy outcomes.

AIMS: Up to 30% of selected heart failure patients do not benefit clinically from cardiac resynchronization therapy (CRT). Left ventricular (LV) wall thickness (WT) analysed using computed tomography (CT) has rarely been evaluated in response to CRT and mitral regurgitation (MR) improvement. We examined the association of LVWT and the ability to reverse LV remodelling and MR improvement after CRT. METHODS AND RESULTS: Fifty-four patients scheduled for CRT underwent pre-procedural CT. Reduced LVWT was defined as WT <6 mm and quantified as a percentage of total LV area. Endpoints were 6-month clinical and echocardiographic response to CRT [New York Heart Association (NYHA) class, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV)], MR improvement and 2-year major adverse cardiac events (MACE). Patients were divided into three groups according to the percentage of LVWT <6 mm area: ≤20%, 20-50%, and ≥50%. At 6 months, 75%, 71%, and 42% of the patients experienced NYHA improvement in the ≤20%, 20-50%, and ≥50% group, respectively. Additionally, ≤20% group presented higher LVEF, LVEDV, and LVESV positive response rate (86%, 59%, and 83%, respectively). Both 20-50% and ≥50% groups exhibited a lower LVEF, LVEDV, and LVESV positive response rate (52% and 42%; 47% and 45%; and 53% and 45%, respectively). Additionally, ≥25% of LVWT <6 mm inclusive of at least one papillary muscle insertion was the only predictor of lack of MR improvement. Lastly, ≥50% group experienced significantly lower 2-year MACE survival free probability. CONCLUSION: WT evaluated using CT could help to stratify the response to CRT and predict MR improvement and outcomes. CLINICAL TRIAL REGISTRATION: NCT01097733.

Plant extract-based diets differently modulate immune responses and resistance to bacterial infection in striped catfish (Pangasianodon hypophthalmus).

A feeding trial was performed to compare the effects of five ethanol herbal extracts (bhumi amla, Phyllanthus amarus Schum and Thonn [Pa]; guava, Psidium guajava L. [Pg]; sensitive plant, Mimosa pudica L. [Mp]; neem, Azadirachta indica A. Juss [Ai] and asthma plant, Euphorbia hirta L. [Eh]) on the immune response and disease resistance against Edwardsiella ictaluri infection of striped catfish (Pangasianodon hypophthalmus). Fish were fed diets supplemented with two doses of each plant extract (0% [basal diet], 0.4% Eh [Eh0.4], 2.0% Eh [Eh2.0], 0.2% Pa [Pa0.2], 1.0% Pa [Pa1.0], 0.2% Pg [Pg0.2], 1.0% Pg [Pg1.0], 0.4% Mp [Mp0.4], 2.0% Mp [Mp2.0], 0.4% Ai [Ai0.4], 2.0% Ai [Ai2.0]) for 8 weeks. Results showed that hematological parameters (total red blood cells, white blood cells, lymphocytes, monocytes, and neutrophils) of fish fed extract-based diets were significantly higher than in those fed the control diet (p < 0.05) after 4 and 8 weeks. Plasma lysozyme activity increased in fish whose diets contained both doses of Eh (p < 0.05) in week 4 (W4), whereas lysozyme activity increased in fish fed 0.2% Pa and Pg, and 2.0% Ai and Eh (p < 0.05) in week 8 (W8). The lysozyme levels in skin mucus did not significantly differ between treatments (p > 0.05) in W4 and after the bacterial challenge test. At the end of the feeding trial, levels of ACH50 significantly increased in most of extract groups compared to the control group (p < 0.05). Total immunoglobulin increased considerably in both the plasma and skin mucus of fish fed extract-supplemented diets after 8 weeks. In addition, dietary supplementation with Pg, Mp, Pa0.2, Eh2.0, and Ai0.4 for 8 weeks considerably reduced the cumulative mortality against E. ictaluri infection in striped catfish. The results suggest that plant extracts possibly modulate the striped catfish immune response in a time and dose dependent manner. Specifically, diets enriched with extracts of P. guajava at 0.2 and 1.0%, or M. pudica at 2.0% for 8 weeks, have great potential for improving striped catfish health by enhancing the immune system and reducing mortality against bacterial challenges.

Screening of immuno-modulatory potential of different herbal plant extracts using striped catfish (Pangasianodon hypophthalmus) leukocyte-based in vitro tests.

Many medicinal plants have been shown to possess biological effects, including immuno-modulatory activities on human and other mammals. However, studies about the potential mechanisms of plant extracts on the humoral and tissular immunities in fish have received less attention. This study aimed to screen the immunestimulating properties of 20 ethanol plant extracts on striped catfish Pangasianodon hypophthalmus leukocytes. The peripheral blood mononuclear cells (PBMCs) and head kidney leukocytes (HKLs) of striped catfish (50 ±â€¯5 g per fish) were stimulated at 10 and 100 µg of each plant extract per mL of cell culture medium. Several humoral immune parameters (lysozyme, complement and total immunoglobulin) were examined at 24-h post stimulation (hps). Furthermore, the responses of four cytokine genes, namely il1ß, ifrγ 2a and b, and mhc class II were assessed by quantitative real-time PCR at 6, 12, 24, and 48 hps. The results showed that lysozyme, complement as well as total immunoglobulin levels in both PBMCs and HKLs were regulated by some of the plant extracts tested in a concentration-dependent manner; some plant extracts induced the highest immune responses at the low dose (10 µg mL-1) while others were more efficient at high dose (100 µg mL-1). Among the extracts, five extracts including garlic Allium sativum L. (As), neem Azadirachta indica A. Juss (Ai), asthma-plant Euphorbia hirta L. (Eh), bhumi amla Phyllanthus amarus Schum. et Thonn (Pa), and ginger Zingiber officinale Rosc (Zo) induced significant changes in the expression of pro-inflammatory cytokine (il1ß), antiviral cytokines (ifrγ 2a and b) and adaptive immune cytokine (mhc class II) in striped catfish cells. Pa always modulated the strongest expression of the four cytokines in PBMCs and HKLs over the whole experimental period (p < 0.05), whereas Zo did not stimulate the mhc class II expression in striped catfish leukocytes throughout experimental periods. These in vitro results demonstrated that some plant extracts could differently modulate great potential immune response in fish, supporting their applications in further in vivo experiments.

The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin.

Aims: Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF. Methods and results: Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n = 6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P > 0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were ∼three-fold higher in coronary sinus compared to systemic vessels (n = 21, all P < 0.0001), while the trans-pulmonary gradient was neutral (n = 5, P = 1.0). Conclusion: The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides.

Prognostic Value of Noninvasive Cardiovascular Testing in Patients With Stable Chest Pain: Insights From the PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).

BACKGROUND: Optimal management of patients with stable chest pain relies on the prognostic information provided by noninvasive cardiovascular testing, but there are limited data from randomized trials comparing anatomic with functional testing. METHODS: In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain and intermediate pretest probability for obstructive coronary artery disease (CAD) were randomly assigned to functional testing (exercise electrocardiography, nuclear stress, or stress echocardiography) or coronary computed tomography angiography (CTA). Site-based diagnostic test reports were classified as normal or mildly, moderately, or severely abnormal. The primary end point was death, myocardial infarction, or unstable angina hospitalizations over a median follow-up of 26.1 months. RESULTS: Both the prevalence of normal test results and incidence rate of events in these patients were significantly lower among 4500 patients randomly assigned to CTA in comparison with 4602 patients randomly assigned to functional testing (33.4% versus 78.0%, and 0.9% versus 2.1%, respectively; both P<0.001). In CTA, 54.0% of events (n=74/137) occurred in patients with nonobstructive CAD (1%-69% stenosis). Prevalence of obstructive CAD and myocardial ischemia was low (11.9% versus 12.7%, respectively), with both findings having similar prognostic value (hazard ratio, 3.74; 95% confidence interval [CI], 2.60-5.39; and 3.47; 95% CI, 2.42-4.99). When test findings were stratified as mildly, moderately, or severely abnormal, hazard ratios for events in comparison with normal tests increased proportionally for CTA (2.94, 7.67, 10.13; all P<0.001) but not for corresponding functional testing categories (0.94 [P=0.87], 2.65 [P=0.001], 3.88 [P<0.001]). The discriminatory ability of CTA in predicting events was significantly better than functional testing (c-index, 0.72; 95% CI, 0.68-0.76 versus 0.64; 95% CI, 0.59-0.69; P=0.04). If 2714 patients with at least an intermediate Framingham Risk Score (>10%) who had a normal functional test were reclassified as being mildly abnormal, the discriminatory capacity improved to 0.69 (95% CI, 0.64-0.74). CONCLUSIONS: Coronary CTA, by identifying patients at risk because of nonobstructive CAD, provides better prognostic information than functional testing in contemporary patients who have stable chest pain with a low burden of obstructive CAD, myocardial ischemia, and events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01174550.

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study.

BACKGROUND: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. METHODS: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. FINDINGS: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210). INTERPRETATION: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. FUNDING: None.

Central Core Laboratory versus Site Interpretation of Coronary CT Angiography: Agreement and Association with Cardiovascular Events in the PROMISE Trial.

Purpose To assess concordance and relative prognostic utility between central core laboratory and local site interpretation for significant coronary artery disease (CAD) and cardiovascular events. Materials and Methods In the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial, readers at 193 North American sites interpreted coronary computed tomographic (CT) angiography as part of the clinical evaluation of stable chest pain. Readers at a central core laboratory also interpreted CT angiography blinded to clinical data, site interpretation, and outcomes. Significant CAD was defined as stenosis greater than or equal to 50%; cardiovascular events were defined as a composite of cardiovascular death or myocardial infarction. Results In 4347 patients (51.8% women; mean age ± standard deviation, 60.4 years ± 8.2), core laboratory and site interpretations were discordant in 16% (683 of 4347), most commonly because of a finding of significant CAD by site but not by core laboratory interpretation (80%, 544 of 683). Overall, core laboratory interpretation resulted in 41% fewer patients being reported as having significant CAD (14%, 595 of 4347 vs 23%, 1000 of 4347; P < .001). Over a median follow-up period of 25 months, 1.3% (57 of 4347) sustained myocardial infarction or cardiovascular death. The C statistic for future myocardial infarction or cardiovascular death was 0.61 (95% confidence interval [CI]: 0.54, 0.68) for the core laboratory and 0.63 (95% CI: 0.56, 0.70) for the sites. Conclusion Compared with interpretation by readers at 193 North American sites, standardized core laboratory interpretation classified 41% fewer patients as having significant CAD. © RSNA, 2017 Online supplemental material is available for this article. Clinical trial registration no. NCT01174550.

Age- and sex-based resource utilisation and costs in patients with acute chest pain undergoing cardiac CT angiography: pooled evidence from ROMICAT II and ACRIN-PA trials.

OBJECTIVES: To determine resource utilisation according to age and gender-specific subgroups in two large randomized diagnostic trials. METHODS: We pooled patient-specific data from ACRIN-PA 4005 and ROMICAT II that enrolled subjects with acute chest pain at 14 US sites. Subjects were randomized between a standard work-up and a pathway utilizing cardiac computed tomography angiography (CCTA) and followed for the occurrence of acute coronary syndrome (ACS) and resource utilisation during index hospitalisation and 1-month follow-up. Study endpoints included diagnostic accuracy of CCTA for the detection of ACS as well as resource utilisation. RESULTS: Among 1240 patients who underwent CCTA, negative predictive value of CCTA to rule out ACS remained very high (≥99.4%). The proportion of patients undergoing additional diagnostic testing and cost increased with age for both sexes (p < 0.001), and was higher in men as compared to women older than 60 years (43.1% vs. 23.4% and $4559 ± 3382 vs. $3179 ± 2562, p < 0.01; respectively). Cost to rule out ACS was higher in men (p < 0.001) and significantly higher for patients older than 60 years ($2860-5935 in men, p < 0.001). CONCLUSIONS: CCTA strategy in patients with acute chest pain results in varying resource utilisation according to age and gender-specific subgroups, mandating improved selection for advanced imaging. KEY POINTS: • In this analysis, CAD and ACS increased with age and male gender. • CCTA in patients with acute chest pain results in varying resource utilisation. • Significant increase of diagnostic testing and cost with age for both sexes. • Cost to rule out ACS is higher in men and patients >60 years. • Improved selection of subjects for cardiac CTA result in more resource-driven implementation.

Aortic Angulation Does Not Impact Outcomes in Self-Expandable or Balloon-Expandable Transcatheter Aortic Valve Replacement.

OBJECTIVES: The role of aortic angulation in attenuating procedural success in balloon-expandable (BE) and self-expandable (SE) transcatheter aortic valve replacement (TAVR) has been controversial. METHODS: We retrospectively assessed patients undergoing SE and BE TAVR who had an aortic angle measured on multidetector computed tomography at a single tertiary referral center. The primary outcome was device success, measured per the Valve Academic Research Consortium-2 criteria. Clinical outcomes at 30 days (including mortality) were also assessed. RESULTS: A total of 251 patients were identified; 182 patients received a BE valve and 69 patients an SE valve. The median aortic angle was 46.8° (range 24.4-70°) in the BE group and 43.3° (range 20-71°) in the SE group. In multivariate logistic regression analysis, aortic angulation did not affect device success. Mortality at 30 days and 12 months and postprocedural clinical outcomes were similarly not associated with aortic angulation. CONCLUSION: In this cohort of patients undergoing BE and SE TAVR over a wide range of aortic angles, we found no associations between angle and device success or any other clinical metrics. Increased aortic angulation does not adversely affect outcomes in BE or SE TAVR.

High-Sensitivity Cardiac Troponin I as a Gatekeeper for Coronary Computed Tomography Angiography and Stress Testing in Patients with Acute Chest Pain.

BACKGROUND: Most patients presenting to the emergency department (ED) with suspected acute coronary syndrome (ACS) undergo noninvasive cardiac testing with a low diagnostic yield. We determined whether a combination of high-sensitivity cardiac troponin I (hs-cTnI) and cardiovascular risk factors might improve selection of patients for cardiac testing. METHODS: We included patients from the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) I and II trials who presented to the ED with acute chest pain and were referred for cardiac testing. Based on serial hs-cTnI measurements and cardiovascular risk factors, we derived and validated the criterion for no need of cardiac testing. We predicted the effect of this criterion on the effectiveness of patient management. RESULTS: A combination of baseline hs-cTnI (<4 ng/L) and cardiovascular risk factors (<2) ruled out ACS with a negative predictive value of 100% in ROMICAT I. We validated this criterion in ROMICAT II, identifying 29% patients as not needing cardiac testing. An additional 5% of patients were identified by adding no change or a decrease between baseline and 2 h hs-cTnI as a criterion. Assuming those patients would be discharged from the ED without cardiac testing, implementation of hs-cTnI would increase ED discharge rate (24.3% to 50.2%, P < 0.001) and decrease the length of hospital stay (21.4 to 8.2 h, P < 0.001), radiation dose (10.2 to 7.7 mSv, P < 0.001), and costs of care (4066 to 3342 US$, P < 0.001). CONCLUSIONS: We derived and validated a criterion for combined hs-cTnI and cardiovascular risk factors that identified acute chest pain patients with no need for cardiac testing and could improve effectiveness of patient management. ClinicalTrials.gov Identifiers: NCT00990262 and NCT01084239.

Soluble CD146 Is a Novel Marker of Systemic Congestion in Heart Failure Patients: An Experimental Mechanistic and Transcardiac Clinical Study.

BACKGROUND: Soluble CD146 (sCD146), is an endothelial marker with similar diagnostic power as natriuretic peptides in decompensated heart failure (HF). While natriuretic peptides are released by the failing heart, sCD146 may be released by veins in response to stretch induced by systemic congestion in HF. This study investigated the source, effects of vascular stress on release and prognostic properties of sCD146 in HF. METHODS: In a peripheral venous stress study, plasma concentrations of sCD146 and N-terminal probrain natriuretic-peptide (NT-proBNP) were measured in 44 HF patients at baseline and after 90 min of unilateral forearm venous congestion. In addition, sCD146 and NT-proBNP were measured in peripheral vein (PV) and coronary sinus (CS) blood samples of 137 HF patients and the transcardiac gradient was calculated. Those patients were followed for major adverse cardiovascular events (MACE) during 2 years. RESULTS: The induction of venous stress was associated with a pronounced increase in circulating concentrations of sCD146 in the congested arm (+60 µg/L) compared to the control arm (+16 µg/L, P = 0.025), while no difference in NT-proBNP concentrations was seen. In contrast to positive transcardiac gradient for NT-proBNP, median sCD146 concentrations were lower in CS than in PV (396 vs 434, P < 0.001), indicating a predominantly extracardiac source of sCD146. Finally, increased PV concentrations of sCD146 were associated with higher risk of MACE at 2 years. CONCLUSIONS: Soluble CD146 is released from the peripheral vasculature in response to venous stretch and may reflect systemic congestion in chronic HF patients.

Mid-regional pro-atrial natriuretic peptide to predict clinical course in heart failure patients undergoing cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) induces reverse cardiac remodelling in heart failure (HF), but many patients receiving CRT remain non-responders. This study assessed the role of amino-terminal-pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide (MR-proANP), and mid-regional-pro-adrenomedullin (MR-proADM) at the time of device implantation to predict favourable clinical course (CRT response and/or risk of MACE) in HF patients receiving CRT. METHODS AND RESULTS: A total of 137 HF patients were prospectively included. Blood was drawn from the coronary sinus (CS) at CRT implantation, and from a peripheral vein (PV) simultaneously and after 6 months. Clinical CRT response at 6 months and major adverse cardiovascular events (MACE) at 2 years were assessed. Baseline PV-levels of MR-proANP (202 vs. 318 pmol/L, P = 0.009) and MR-proADM (843 vs. 1112 pmol/L, P = 0.02) were lower in CRT responders compared with non-responders. At 6 months, CRT responders showed a decrease in MR-proANP levels, compared with an increase in non-responders (-32 vs. +7 pmol/L, P = 0.02). During the same period, NT-proBNP decreased by a similar way in responders and non-responders, while MR-proADM was unchanged in both groups. High baseline MR-proANP, either in PV (OR 0.41, 95% CI 0.24-0.71, P = 0.002) or CS (OR 0.32, 95% CI 0.15-0.70, P = 0.005) was associated with reduced likelihood of CRT response. Furthermore, PV and CS levels of NT-proBNP, MR-proANP, and MR-proADM were all associated with increased risk of 2-year MACE (all P < 0.01). CONCLUSION: Mid-regional-pro-atrial natriuretic peptide may assist prediction of clinical course in HF patients undergoing CRT implantation. Low circulating MR-proANP at the time of device implantation is associated with CRT response and more favourable outcome.