Normal Values and Reference Ranges for the Ratio of Transmitral Early Filling Velocity to Early Diastolic Strain Rate: The Copenhagen City Heart Study.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has recently emerged as a measure of left ventricular filling pressure. Reference values are needed for this new parameter for it to be used clinically. METHODS: Healthy participants from a prospective general population study, the Fifth Copenhagen City Heart Study, were assessed to establish reference values for E/e'sr derived from two-dimensional speckle-tracking echocardiography. The prevalence of abnormal E/e'sr was assessed in participants with cardiovascular risk factors or specific diseases. RESULTS: The population comprised 1,623 healthy participants (median age, 45; interquartile range, 32-56; 61% female). The upper reference limit for E/e'sr in the population was 79.6 cm. Following multivariable adjustment, male participants exhibited significantly higher E/e'sr than female participants (upper reference limit for male participants, 83.7 cm; for female participants, 76.5 cm). For both sexes, E/e'sr increased in a curvilinear fashion with age such that the largest increases in E/e'sr were observed in participants >45 years. In the entire CCHS5 population with E/e'sr available (n = 3,902), increasing age, body mass index, systolic blood pressure, male sex, estimated glomerular filtration rate, and diabetes were associated with E/e'sr (all P < .05). Total cholesterol was associated with a less steep increase in E/e'sr. Abnormal E/e'sr was seldomly observed in participants with normal diastolic function but became more frequent in participants with increasing grades of diastolic dysfunction (normal, mild, moderate, severe [abnormal E/e'sr for each grade: 4.4% vs 20.0% vs 16.2% vs 55.6%, respectively]). CONCLUSION: The E/e'sr differs between sexes and is age dependent such that E/e'sr increases with advancing age. Therefore, we established sex- and age-stratified reference values for E/e'sr.

The clinical application of the ratio of transmitral early filling velocity to early diastolic strain rate: a systematic review and meta-analysis.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has recently emerged as a novel and accurate non-invasive measure of left ventricular (LV) filling pressure. This systematic review and meta-analysis aimed to give an overview of the possible clinical implications of E/e'sr. METHODS: We conducted a systematic review and meta-analysis of all studies involving E/e'sr. Of 598 identified studies, 16 met our inclusion criteria. Studies involving E/e'sr either investigated its prognostic value (n = 9) or its correlation with invasively measured LV filling pressure (n = 7). RESULTS: The pooled meta-analysis showed a significant correlation between E/e'sr and pulmonary capillary wedge pressure (PCWP) measured invasively across the studies assessing this relationship (Cohen's d = 3.90 95% CI [2.38-6.39], p < 0.001) and between E/e'sr and left ventricle end-diastolic pressure (LVEDP) measured invasively across the studies assessing this relationship (Cohen's d = 5.30 95% CI [2.83-9.96], p < 0.001). The pooled analysis of the prognostic studies showed that E/e'sr was a significant predictor of adverse outcomes after multivariable adjustment across the different study populations in a random effects model (overall estimated HR: 1.58 95% CI [1.28-1.96], p < 0.001, per 1 m increase). CONCLUSION: E/e'sr correlates well with invasive measures of LV filling pressure. In addition, E/e'sr provides significant prognostic information across various patient populations. Further studies are needed to test if E/e'sr has an advantage to E/e'.

Cardiac function assessed by myocardial deformation in adult polycystic kidney disease patients.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease. METHODS: A total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (- 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group. RESULTS: There was a significantly worse GLS in the ADPKD patients (mean: - 17.8 ± 2.5%) compared to the healthy controls (mean: - 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10-10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01-1.10], p = 0.024), htTKV (OR: 1.07 [1.01-1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00-1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11-2.04], p = 0.009), and ß-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27-14.71], p < 0.001) and ß-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02-1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00-1.06], p = 0.027) and ß-blocker use (OR: 17.12 [2.15-136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only ß-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant. CONCLUSION: Higher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.

Scaling-up psychological interventions in resource-poor settings: training and supervising peer volunteers to deliver the 'Thinking Healthy Programme' for perinatal depression in rural Pakistan.

BACKGROUND: There is a scarcity of specialist trainers and supervisors for psychosocial interventions in low- and middle-income countries. A cascaded model of training and supervision was developed to sustain delivery of an evidence-based peer-delivered intervention for perinatal depression (the Thinking Healthy Programme) in rural Pakistan. The study aimed to evaluate the model. METHODS: Mixed methods were employed as part of a randomised controlled trial of the intervention. Quantitative data consisted of the peers' competencies assessed during field training and over the implementation phase of the intervention, using a specially developed checklist. Qualitative data were collected from peers and their trainers through 11 focus groups during the second and third year of intervention rollout. RESULTS: Following training, 43 peers out of 45 (95%) achieved at least a 'satisfactory' level of competency (scores of ⩾70% on the Quality and Competency Checklist). Of the cohort of 45 peers initially recruited 34 (75%) were retained over 3 years and showed sustained or improved competencies over time. Qualitatively, the key factors contributing to peers' competency were use of interactive training and supervision techniques, the trainer-peer relationship, and their cultural similarity. The partnership with community health workers and use of primary health care facilities for training and supervision gave credibility to the peers in the community. CONCLUSION: The study demonstrates that lay-workers such as peers can be trained and supervised to deliver a psychological intervention using a cascaded model, thus addressing the barrier of scarcity of specialist trainers and supervisors.

Cardiac MRI T2* in Liver Transplant Candidates: Application and Performance of a Novel Imaging Technique to Identify Patients at Risk for Poor Posttransplant Cardiac Outcomes.

BACKGROUND: In end-stage liver disease, alterations in iron metabolism can lead to iron overload and development of iron overload cardiomyopathy. In liver transplant candidates, evaluation for cardiac iron overload and dysfunction can help to identify candidates at increased risk for peritransplant morbidity and mortality, though recommendations for pretransplant evaluation of cardiac iron overload are not standardized. Cardiac Magnetic Resonance Imaging T2* (CMRI-T2*) is a validated method to quantify cardiac iron deposition, with normal T2* value of 20 ms or greater. In this study, we sought to identify the incidence and predictors of iron overload by CMRI-T2* and to evaluate the impact of cardiac and iron overload on morbidity and mortality after liver transplantation. METHODS: In this retrospective single-center cohort study, all liver transplant candidates who underwent a pretransplant CMRI-T2* between January 1, 2008, and June 30, 2016, were included to analyze the association between clinical characteristics and low T2* using logistic regression. RESULTS: One hundred seventy-nine liver transplant candidates who received CMRI-T2* were included. Median age was 57 years, 73.2% were male, and 47.6% were white. 49.7% had hepatitis C and 2.8% had hemochromatosis. Median Model for End-Stage Liver Disease score was 25. 65.2% were Child-Pugh C. In multivariable logistic regression, T2* less than 20 ms (n = 35) was associated with Model for End-Stage Liver Disease score of 25 or greater (odds ratio [OR], 3.65; P = 0.007), Child-Pugh C (OR, 3.42; P = 0.03), and echocardiographic systolic ejection fraction less than 65% (OR, 2.24; P = 0.01). Posttransplant heart failure occurred exclusively in recipients with T2* less than 15 ms. Survival was worse in T2* 10 to 14.9 versus T2* of 20 ms or greater (hazard ratio, 3.85; P = 0.003), but not for 15 to 19.9 versus T2* of 20 ms or greater. CONCLUSIONS: Severity of liver disease and systolic dysfunction is associated with T2* less than 20 ms, though there was no difference in posttransplant outcomes between T2* 15 to 19.9 and T2* 20 ms or greater, suggesting that individuals with T2* of 15 ms or greater may be suitable transplant candidates. CMRI-T2* is an additional diagnostic tool in evaluating transplant candidates at high risk for posttransplant cardiac complications.

TNFα depleting therapy improves fertility and animal welfare in TNFα-driven transgenic models of polyarthritis when administered in their routine breeding.

Transgenic tumour necrosis factor alpha (TNFα)-driven models of polyarthritis such as the TNFΔARE mouse have proven to be invaluable in delineating aspects of inflammatory disease pathophysiology in humans. Unfortunately, the onset of joint destruction and inflammation in these models represents a significant detriment to breeding management. We examined whether TNFα depleting therapy 'infliximab' might represent a significant refinement in routine breeding. Clinical scores of joint inflammation were assessed in TNFΔARE males receiving either infliximab (10 mg/kg) or saline by twice-weekly intraperitoneal injection. Joint histology and bone morphology were assessed by histological analysis and micro-computed tomography (CT), respectively. Analysis of breeding was examined retrospectively in TNFΔARE males prior to, and following, regular introduction of infliximab. Clinical scores of inflammation were significantly reduced in TNFΔARE males receiving infliximab (control 6.6 arbitrary units [AU] ± 0.88 versus infliximab 4.4 AU ± 1.4; P < 0.05), while measures of pannus invasion and bone erosion by histology and micro-CT were markedly reduced. In the breeding groups, TNFΔARE males receiving infliximab injections sired more litters over their breeding lifespan (control 1.69 ± 0.22 versus infliximab 3.00 ± 0.19; P < 0.005). Furthermore, prior to infliximab, TNFΔARE males had a 26% risk of failing to sire any litters. This was reduced to 7% after the introduction of infliximab. This study is the first to report that regular administration of infliximab is effective at suppressing disease activity and improving animal welfare in TNFΔARE animals. In addition, we have shown that infliximab is highly efficacious in improving breeding behaviour and increasing the number of litters sired by TNFΔARE males.

Caffeine accelerates recovery from general anesthesia via multiple pathways.

Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP]i)-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A2A receptor blockade and [cAMP]i elevation play a role in caffeine's ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response.NEW & NOTEWORTHY Currently, there is no method to accelerate emergence from anesthesia. Patients "wake" when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that caffeine is effective even at high levels of anesthetic. We also show that caffeine operates by both elevating intracellular cAMP levels and by blocking adenosine receptors. This complicated pharmacology makes caffeine especially effective in accelerating emergence from anesthesia.

Selective association of electrocardiographic abnormalities with insulin sensitivity and beta-cell function in type 2 diabetes mellitus: a cross-sectional analysis.

BACKGROUND: We investigated the association of electrocardiographic (ECG) abnormalities with markers of insulin resistance and pancreatic beta-cell dysfunction in a cross-sectional study of type 2 diabetes patients. METHODS: Electrocardiographic criteria were evaluated in the Penn Diabetes Heart Study participants (n = 1671; 64% male; 61% Caucasian), including a sub-sample (n = 710) that underwent oral glucose tolerance testing. The Matsuda Insulin Sensitivity Index and homeostasis model assessment of insulin resistance (HOMA-IR) estimated insulin sensitivity; Insulinogenic Index and homeostasis model assessment of beta-cell function assessed beta-cell function. Multivariable regression modelling was used to analyse associations of ECG changes with these indices. RESULTS: In unadjusted analyses, subjects in the highest quartile of Matsuda index had the lowest prevalence of Q-waves (6.3% versus 15.3%, p = 0.005). In adjusted models, an inverse association was seen between Q-waves and log Matsuda index [one standard deviation increase; OR = 0.59 (95% CI 0.43-0.87 p = 0.001)]. In the full Penn Diabetes Heart Study, there was a direct association between Q-waves and HOMA-IR [one standard deviation increase; OR = 1.43 (95% CI 1.13-1.81, p = 0.003)]. In adjusted models, left ventricular hypertrophy also was inversely associated with Matsuda index and directly with HOMA-IR. Higher Insulinogenic Index scores were associated with a lower prevalence of nonspecific ST changes [OR = 0.78 (95% CI 0.62-0.98, p = 0.032)]. CONCLUSIONS: In type 2 diabetic patients, both oral glucose tolerance testing-derived and HOMA-derived measures of insulin resistance were associated with pathologic Q-waves and left ventricular hypertrophy on ECGs. Copyright © 2016 John Wiley & Sons, Ltd.

A comprehensive evaluation of machine learning techniques for cancer class prediction based on microarray data.

Prostate cancer is among the most common cancer in males and its heterogeneity is well known. The genomic level changes can be detected in gene expression data and those changes may serve as standard model for any random cancer data for class prediction. Various techniques were implied on prostate cancer data set in order to accurately predict cancer class including machine learning techniques. Large number of attributes but few numbers of samples in microarray data leads to poor training; therefore, the most challenging part is attribute reduction or non-significant gene reduction. In this work, a combination of interquartile range and t-test is used for attribute reduction. Further, a comprehensive evaluation of ten state-of-the-art machine learning techniques for their accuracy in class prediction of prostate cancer is done. Out of these techniques, Bayes Network outperformed with an accuracy of 94.11% followed by Naïve Bayes with an accuracy of 91.17%.

Ascending and descending thoracic aorta calcification in type 2 diabetes mellitus.

BACKGROUND: Calcification of the thoracic aorta is a risk factor for cardiovascular disease and peripheral arterial disease but has not been well studied in diabetics. In addition, many studies consider aortic calcium as a single anatomic entity, whereas calcification of the ascending and descending portions of the thoracic aorta may represent separate phenotypes. We sought to characterize the prevalence of ascending and descending aortic calcium among diabetics and to assess their associations with cardiovascular risk factors, coronary artery calcium, and peripheral arterial disease. METHODS: Within the Penn Diabetes Heart Study, a cross-sectional study of subjects with type 2 diabetes mellitus but without coronary or renal disease, we quantified Agatston scores of the ascending and descending thoracic aorta in 1739 subjects (63% male, 61% Caucasian). Multivariate logistic and Tobit regressions were used to assess associations with cardiovascular risk factors, coronary calcium, and peripheral arterial disease. RESULTS: Of all subjects, 54% had thoracic aortic calcium; of these, 37% had calcium solely in the ascending thoracic aorta and 20% solely in the descending thoracic aorta. In multivariate regression, age, Caucasian race, systolic blood pressure, low-density lipoprotein cholesterol, smoking, and diabetes duration were independently associated with calcium of both the ascending and descending thoracic aorta (P < .001 for all). Ascending and descending aortic calcium were each independently associated with coronary calcium in multivariate regression, but only calcification of the descending thoracic aortic was associated with low ankle-brachial index. CONCLUSION: Ascending and descending thoracic aortic calcium have similar associations with traditional cardiovascular risk factors in diabetics and are independently associated with coronary artery calcium. Only calcium in the descending aorta is associated with peripheral arterial disease. Delineation of both phenotypes may provide information about the individualized vascular disease and risk profile of patients with type 2 diabetes mellitus.

Outcome of early revascularization surgery in patients with ST-elevation myocardial infarction.

OBJECTIVES: To compare morbidity and mortality of patients with ST-elevation myocardial infarction (MI) undergoing coronary artery bypass graft (CABG) surgery within 24 hours with those who had surgery delayed >24 hours. BACKGROUND: Patients with ST-elevation MI are currently managed by emergency percutaneous coronary intervention (PCI). If PCI is unsuccessful, or if there is severe coronary artery disease not amenable to PCI, CABG is considered. If the patient is clinically stable, surgeons wait several days before performing surgery, as very early surgery carries a prohibitive risk. METHODS: One hundred and eighty-four patients with acute ST elevation MI (STEMI) who had undergone CABG were divided into two groups based on their surgery timing (<24 hours vs. >24 hours). Mortality and complication rates were studied between the two groups by Fischer test. Time-to-event analyses were performed for five primary variables: all-cause mortality, cardiac events, congestive heart failure, stroke, and renal failure. RESULTS: At one month post-CABC, all-cause mortality was noted in 10.6% of patients who had CABG within 24 hours of STEMI diagnosis, compared with 8.9% in patients who had CABG after 24 hours (P = 0.3). Cardiac events including re-exploration, atrial fibrillation, graft occlusion, and arrhythmias requiring shock occurred in 17.1% versus 13.9% between the two groups, respectively (P = 0.68). One year post-coronary artery bypass surgery, there was no difference in individual or combined events between the two groups. CONCLUSIONS: In patients with ST-elevation myocardial infarction who required emergency coronary artery bypass surgery, there was no difference in procedure complications or mortality between early (within 24 hours) or later (more than 24 hours). That was noted at one month and one year after the index myocardial infarction.

Leptin and incident cardiovascular disease: the Multi-ethnic Study of Atherosclerosis (MESA).

OBJECTIVE: Higher serum leptin levels have been associated with a modestly higher incidence of cardiovascular disease in studies involving mostly Caucasian men. We aimed to assess the hypothesis that higher baseline levels of serum leptin are associated with higher risk of future cardiovascular disease in a diverse cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a modern, community-based, ethnically-diverse, and sex-balanced prospective cohort study of US adults free from cardiovascular disease. Serum leptin was measured in an ancillary study in 2002-2005. This analysis included 1905 MESA participants with baseline leptin and incident cardiovascular event data. Leptin levels were modeled as a log-transformed continuous variable and multivariable-adjusted Cox regression was performed for the primary outcome of hard cardiovascular disease, including coronary heart disease and stroke. RESULTS: The median follow-up was 7.6 years (25th-75th 7.1-8.3) with 7051 and 6738 person-years of follow-up in women and men. A hard cardiovascular disease event occurred in 47 women and 63 men. The age- and ethnicity-adjusted hazard ratio estimates for a 1 standard deviation increase in ln(leptin) were 1.16 in women (95% CI 0.78-1.73, p = 0.46) and 0.91 (95% CI 0.69-1.20, p = 0.51) in men. Pooling sexes, and adjusting for sex in addition to age and ethnicity, estimates were 0.98 (95% CI 0.78-1.23, p = 0.89). With additional adjustment for cardiovascular risk factors, the results remained nonsignificant: 0.87 (95% CI 0.68-1.11, p = 0.26). CONCLUSION: In conclusion, in a modern, US prospective cohort study of multi-ethnic women and men of multi-ethnic backgrounds, leptin levels are not associated with incident cardiovascular events.

Absorbed radiation dose in radiosensitive organs using 64- and 320-row multidetector computed tomography: a comparative study.

Aim. To determine absorbed radiation dose (ARD) in radiosensitive organs during prospective and full phase dose modulation using ECG-gated MDCTA scanner under 64- and 320-row detector modes. Methods. Female phantom was used to measure organ radiation dose. Five DP-3 radiation detectors were used to measure ARD to lungs, breast, and thyroid using the Aquilion ONE scanner in 64- and 320-row modes using both prospective and dose modulation in full phase acquisition. Five measurements were made using three tube voltages: 100, 120, and 135 kVp at 400 mA at heart rate (HR) of 60 and 75 bpm for each protocol. Mean acquisition was recorded in milligrays (mGy). Results. Mean ARD was less for 320-row versus 64-row mode for each imaging protocol. Prospective EKG-gated imaging protocol resulted in a statistically lower ARD using 320-row versus 64-row modes for midbreast (6.728 versus 19.687 mGy, P < 0.001), lung (6.102 versus 21.841 mGy, P < 0.001), and thyroid gland (0.208 versus 0.913 mGy; P < 0.001). Retrospective imaging using 320- versus 64-row modes showed lower ARD for midbreast (10.839 versus 43.169 mGy, P < 0.001), lung (8.848 versus 47.877 mGy, P < 0.001), and thyroid gland (0.057 versus 2.091 mGy; P < 0.001). ARD reduction was observed at lower kVp and heart rate. Conclusions. Dose reduction to radiosensitive organs is achieved using 320-row compared to 64-row modes for both prospective and retrospective gating, whereas 64-row mode is equivalent to the same model 64-row MDCT scanner.

Cancerogenesis Risks between 64 and 320 Row Detector CT for Coronary CTA Screening.

OBJECTIVES: This study compares cancerogenesis risks posed by the 64 row detector and the 320 row detector computed tomography scanners used during coronary computed tomography angiography (CCTA) following decennial screening guidelines. MATERIAL AND METHODS: Data of the radiation absorbed after CCTA by lung, thyroid, and female breast in patients between 50 and 70 years of age obtained from prior published literature for the 64 row CT scanner were compared with data from our study using 320 row detector CT scanner. Data from the 64 row and the 320 row detector CT scanners was used to determine lifetime attributable risks (LAR) of cancer based on the biological effects of ionizing radiation (BEIR) VII report. RESULTS: The relative reduction of LAR (%) for 50-, 60-, and 70-year-old patients undergoing scanning with the 320 row detector CT scanner was 30% lower for lung, and more than 50% lower for female breast when compared with results from 64 row detector CT scanner. The use of 320 row detector CT would result in a combined cumulative cancer incidence of less than 1/500 for breast in women and less than 1/1000 for lung in men; By comparison, this is much lower than other more common risk factors: 16-fold for lung cancer in persistent smokers, 2-fold for breast cancer with a first degree family member history of breast cancer, and 10-fold for thyroid cancer with a family member with thyroid cancer. Decennial screening would benefit at least 355,000 patients from sudden cardiac death each year, 94% of whom have significant coronary artery disease, with at least one stenosis >75%. LAR for thyroid cancer was negligible for both scanners. CONCLUSION: Lung and female breast LAR reductions with 320 row detector compared with 64 row detector CT are substantial, and the benefits would outweigh increased cancer risks with decennial screening in the age group of 50-70 years.

Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits.

OBJECTIVE: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) are secreted proteins that inhibit lipoprotein lipase in vitro. Genetic variants at the ANGPTL3 and ANGPTL4 gene loci are significantly associated with plasma lipid traits. The aim of this study was to evaluate the association of plasma ANGPTL3 and ANGPTL4 concentrations with lipid and metabolic traits in a large community-based sample. APPROACH AND RESULTS: Plasma ANGPTL3 and ANGPTL4 levels were measured in 1770 subjects using a validated ELISA assay. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, sex, and race were performed. ANGPTL3 levels were significantly positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels (both P<2×10(-5)) but not triglycerides. In contrast, ANGPTL4 levels were significantly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (both P<2×10(-5)) and positively associated with triglycerides (P=0.003). In addition, ANGPTL4, but not ANGPTL3, levels were significantly positively associated with fasting blood glucose and metabolic syndrome. CONCLUSIONS: Despite having similar biochemical effects in vitro, plasma ANGPTL3 and ANGPTL4 concentrations have nearly opposite relationships with plasma lipids. ANGPTL4 is strongly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and positively with multiple features of the metabolic syndrome including triglycerides, whereas ANGPTL3 is positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and not with metabolic syndrome traits including triglycerides. Although ANGPTL3 and ANGPTL4 both inhibit lipoprotein lipase in vitro and influence lipoprotein metabolism in vivo, the physiology of these related proteins and their effects on lipoproteins is clearly divergent and complex.

Assessment of liver fat in an obese patient population using noncontrast CT fat percent index.

OBJECTIVE: To develop a simplified method to quantify liver fat using computed tomography (CT) fat % index (CTFPI) compared to liver spleen method (CTL/S, CTL-S). METHODS: Noncontrast CT of the liver was performed in 89 patients (overweight, obese, severely obese) to quantify fat, using the following: CTFPI=[(65-patient HU)/65]×100, normal live r=65 HU. RESULTS: There was a strong linear correlation between CTFPI and the standard method of assessing liver fat using CTL/S (r=-0.901), CTL-S (r=-0.911). Hepatic HU and CTFPI were significantly different in the severely obese group compared to other two groups (P<.05). CONCLUSION: Significant correlation indicates equal diagnostic accuracy of the two methods in appropriately calibrated scanners.

Differential associations of oral glucose tolerance test-derived measures of insulin sensitivity and pancreatic ß-cell function with coronary artery calcification and microalbuminuria in type 2 diabetes.

OBJECTIVE We evaluated relationships of oral glucose tolerance testing (OGTT)-derived measures of insulin sensitivity and pancreatic ß-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease. RESEARCH DESIGN AND METHODS A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and ß-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria. RESULTS The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio -0.78 [95% CI -1.51 to -0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30-0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes. CONCLUSIONS Lower ß-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.

Non-compressible arterial disease and the risk of coronary calcification in type-2 diabetes.

OBJECTIVE: Ankle-brachial index (ABI) screening is recommended for the detection of asymptomatic peripheral arterial disease (PAD) in at-risk populations, including diabetics. A low ABI identifies obstructive lower extremity vascular disease and predicts CVD events and increased mortality. A high ABI represents non-compressible arterial disease (NCAD), and is also associated with increased mortality and vascular events. Our objective is to investigate whether low and high ABI have distinct patterns of association with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis in individuals with type-II diabetes mellitus. METHODS: The Penn Diabetes Heart Study (PDHS) is a prospective observational cohort of diabetic individuals without clinically evident CVD. Multivariate logistic and Tobit linear regression were used to compare CVD risk factors and coronary artery (CAC) among 1863 subjects with PAD (ABI ≤ 0.9), NCAD (ABI ≥ 1.4 or non-compressible) or normal ABI (0.91-1.39). RESULTS: Compared to those with normal ABI, PAD was associated with smoking, obesity, and lower HDL-c; while diabetes duration and reduced renal function were associated with NCAD. Both PAD and NCAD were independently associated with increased CAC compared to those with normal ABI, and these relationships were not attenuated in multiply adjusted models. CONCLUSION: NCAD bears a distinct relationship to traditional CVD risk factors among diabetics, though like PAD is independently associated with increased CAC. These findings support the recognition of NCAD as a high-risk phenotype and provide additional relevance to ABI screening in diabetics.