Integrated Discrimination Index Research Articles

The fat mass and obesity-associated (FTO) gene variant rs9939609 predicts long-term incidence of cardiovascular disease and related death independent of the traditional risk factors

Objective and methods The impact of the rs9939609 FTO variant on cardiovascular events was investigated in the 19-year follow-up of subjects recruited to the OPERA study.Results A total of 212 cardiovascular disease (CVD) and 152 coronary heart disease (CHD) events or deaths occurred during follow-up. The logistic regression analysis revealed that among the AA genotype the incidence of CHD (OR 1.905; 95% CI 1.250–2.903, p = 0.001) and CVD (OR 1.849; 1.265–2.702, p = 0.003) events or death was significantly higher when adjusted for age, sex, and study group. After further adjustment with BMI, smoking status, systolic blood pressure, and low-density lipoprotein cholesterol, the higher incidence of CHD and CVD events or death among subjects with the AA genotype remained significant (OR 1.895; p = 0.002 and p = 0.004, respectively). In Cox regression analysis, the AA genotype displayed a higher rate of CVD and CHD death when the model was adjusted for sex, age, and study group (p = 0.006 and p = 0.046). FTO rs9939609 AA genotype improved the C-index of the final predictive model from 0.709 to 0.715. In reclassification analyses, the integrated discrimination index was significant 0.011 (p = 0.010).Conclusion The AA genotype of FTO rs9939609 seems to be associated with a higher risk of CVD, and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis.Key messagesThe AA genotype of FTO rs9939609 seems to be associated with a higher risk of cardiovascular disease.This phenomenon seems to be independent of the traditional risk factors for atherosclerosis.

Prognostic Value of Coronary Flow Reserve in Patients with Dialysis-Dependent ESRD

Capillary rarefaction of the coronary microcirculation is a consistent phenotype in patients with dialysis-dependent ESRD (dd-ESRD) and may help explain their excess mortality. Global coronary flow reserve (CFR) assessed by positron emission tomography (PET) is a noninvasive, quantitative marker of myocardial perfusion and ischemia that integrates the hemodynamic effects of epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. We tested whether global CFR provides risk stratification in patients with dd-ESRD. Consecutive patients with dd-ESRD clinically referred for myocardial perfusion PET imaging were retrospectively included, excluding patients with prior renal transplantation. Per-patient CFR was calculated as the ratio of stress to rest absolute myocardial blood flow. Multivariable Cox proportional hazards models, including age, overt cardiovascular disease, and myocardial scar/ischemia burden, were used to assess the independent association of global CFR with all-cause and cardiovascular mortality. The incremental value of global CFR was assessed with relative integrated discrimination index and net reclassification improvement. In 168 patients included, median global CFR was 1.4 (interquartile range, 1.2-1.8). During follow-up (median of 3 years), 36 patients died, including 21 cardiovascular deaths. Log-transformed global CFR independently associated with all-cause mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.14; P<0.001) and cardiovascular mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.15; P=0.002). For all-cause mortality, addition of global CFR resulted in risk reclassification in 27% of patients. Thus, global CFR may provide independent and incremental risk stratification for all-cause and cardiovascular mortality in patients with dd-ESRD.

Genome-wide association study based risk prediction model in predicting lung cancer risk in Chinese

To evaluate the predictive power of risk model by combining traditional epidemiological factors and genetic factors. Our previous GWAS data of lung cancer in Chinese were used in training set (Nanjing and Shanghai: 1473 cases vs. 1962 control) and testing set (Beijing and Wuhan: 858 cases vs. 1 115 control). All the single nucleotide polymorphisms (SNPs) associated with lung cancer risk were systematically selected and stepwise logistic regression analysis was used to select independent factors in the training set. The wGRS (weighted genetic score) was further used to calculate genetic risk score. To evaluate the contribution of the genetic factors, 3 risk models were established by using the training set, i.e. smoking model (based on smoking status) , genetic risk model (based on genetic risk score) and combined model (based on smoke and genetic risk score). The predictability of the models were evaluated by the areas under the receiver operating characteristic (ROC) curves, area under curve (AUC), net reclassification improvement (NRI) and integrated discrimination index (IDI). Besides, the results were further verified in the testing set. In the training set, it was found that the AUC of the smoking, genetic risk and combined models were 0.65 (0.63-0.66), 0.60 (0.59-0.62) and 0.69 (0.67-0.71), respectively. Compared with combined model, the predictive power of other two models significantly declined, the difference was statistically significant (P<0.001). Furthermore, compared with the smoking model, the NRI of the combined model increased by 4.57% (2.23%-6.91%) and IDI increased by 3.11% (2.52%-3.69%) in the training set, the difference was statistically significant (P<0.001). Similarly, in the testing set NRI increased by 2.77%, the difference was not statistically significant (P=0.069) , and IDI increased by 3.16%, the difference was statistically significant (P<0.001). This study showed that combining 14 genetic variants with traditional epidemiological factors could improve the predictive power of risk model for lung cancer. The model could be used in the screening of high-risk population of lung cancer in Chinese and provide evidence for the early diagnosis and treatment of lung cancer.

Prognostic impact of neutrophil gelatinase-associated lipocalin and B-type natriuretic in patients with ST-elevation myocardial infarction treated by primary PCI: a prospective observational cohort study

ObjectivesNeutrophil gelatinase-associated lipocalin (NGAL) from a pathophysiological perspective connects various pathways that affect the prognosis after myocardial infarction. The objective was to evaluate the benefits of measuring NGAL for prognostic...

Exercise Capacity and Heart Rate Responses to Exercise as Predictors of Short-Term Outcome Among Patients With Stable Coronary Artery Disease

Although exercise capacity (EC) and autonomic responses to exercise predict clinical outcomes in various populations, they are not routinely applied in patients with coronary artery disease (CAD). We hypothesized that the composite index of EC and exercise heart rate responses would be a powerful determinant of short-term risk in CAD. Patients with angiographically documented stable CAD and treated with β blockers (n = 1,531) underwent exercise testing to allow the calculation of age- and gender-adjusted EC, maximal chronotropic response index (CRI), and 2-minute postexercise heart rate recovery (HRR, percentage of maximal heart rate). Cardiovascular deaths and hospitalization due to heart failure, registered during a 2-year follow-up (n = 39, 2.5%), were defined as the composite primary end point. An exercise test risk score was calculated as the sum of hazard ratios related to abnormal (lowest tertile) EC, CRI, and HRR. Abnormal EC, CRI, and HRR predicted the primary end point, involving 4.5-, 2.2-, and 6.2-fold risk, respectively, independently of each other. The patients with intermediate and high exercise test risk score had 11.1-fold (95% confidence interval 2.4 to 51.1, p = 0.002) and 25.4-fold (95% confidence interval 5.5 to 116.8, p <0.001) adjusted risk for the primary end point in comparison with the low-risk group, respectively. The addition of this risk score to the established risk model enhanced discrimination by integrated discrimination index and reclassification by categorical and continuous net reclassification index (p <0.001 for all). In conclusion, the composite index of EC and heart rate responses to exercise and recovery is a powerful predictor of short-term outcome in patients with stable CAD.

Abstract 265: Lipoprotein (a) Predicts Carotid Plaque, Extent of Coronary Artery Disease and Improves Discrimination and Risk Reclassification Beyond Conventional Risk Factors

Background and Aims: Lipoprotein (a) [Lp(a)] has been identified as a risk factor for cardiovascular disease (CVD). We examined whether Lp(a) predicts subclinical atherosclerosis, extent of coronary artery disease and modifies discrimination and risk reclassification of CVD beyond conventional risk factors. Methods: Plasma Lp(a) and CVD risk factors were assessed in a random community-based cohort (Carotid Ultrasound Disease Assessment Study, CUDAS) and a cohort with premature angiographically defined coronary artery disease (CAD) (Carotid Ultrasound in Patients with Ischemic Heart Disease, CUPID). Carotid intima media thickness (IMT) and focal plaque were assessed by carotid B-mode ultrasound in both cohorts. The extent and severity of CAD was determined by the modified Gensini and Coronary Artery Stenosis ≥20% (CAGE) scores in CUPID. Results: In pooled analyses of 1414 individuals (830 men and 584 women) aged 20 to 70 years, Lp(a) was associated with risk of myocardial infarction and/or stroke [Odds Ratio (95% Confidence Intervals)][1.14 (1.05, 1.24)] and presence of focal plaque [1.08 (1.01, 1.16)], independent of age, gender and cardiometabolic risk factors (including body mass index, triglycerides, smoking, diabetes, hypertension, hypercholesterolemia and family history of CVD). Lp(a) was not associated with IMT. In CUPID, Lp(a) was an independent determinant of the Gensini score and in CUPID men, the CAGE ≥20% score (all P&lt;0.01). The addition of Lp(a) to the basic model (age, gender and cardiometabolic risk factors) improved the C-statistics, integrated discrimination index and category-free net reclassification improvement for myocardial infarction and/or stroke. Conclusions: Lp(a) predicts risk of myocardial infarction and/or stroke, carotid plaque and extent of CAD. The addition of Lp(a) improves discrimination and risk reclassification of myocardial infarction and/or stroke beyond conventional risk factors.

Clinical significance of serum bilirubin and gamma-glutamyltransferase levels on coronary atherosclerosis assessed by multidetector computed tomography

Background and aimsLow bilirubin and high gamma-glutamyltransferase (GGT), which are endogenous markers of oxidative stress, confer a higher risk of cardiovascular disease (CVD). We investigated associations between serum concentrations of bilirubin, GGT and coronary atherosclerosis. Methods and resultsA cross-sectional analysis was performed on 1520 subjects who underwent multidetector computed tomography scans. Coronary atherosclerosis was assessed by coronary artery calcium score (CACS) and obstructive coronary artery disease (OCAD), was defined as the presence of coronary artery stenosis of ≥50%. Total bilirubin (TB) level was negatively correlated with CACS and coronary stenosis whereas GGT level was positively correlated with CACS in men. However, there was no correlation between TB, GGT levels and either CACS or coronary artery stenosis in women. In a multivariate-adjusted model, TB level was inversely associated with a CACS > 100 [odds ratio (OR) per log standard deviation (SD), 0.67; 95% confidence interval (CI), 0.52–0.87], and OCAD (OR per log SD, 0.77; 95% CI, 0.62–0.95) in men. By contrast, GGT level was positively associated with a CACS > 100 (OR per log SD, 1.35; 95% CI, 1.05–1.73) but not with OCAD. Adding TB and GGT to the conventional risk factors increased predictive accuracy for CACS > 100 (net reclassification improvement index [NRI] = 13.1%, P = 0.026; integrated discrimination index [IDI] = 0.024, P = 0.001) and for OCAD (NRI = 12.6%, P = 0.026; IDI = 0.010, P = 0.013). ConclusionsLow TB and high GGT levels were concomitantly associated with coronary atherosclerosis in Korean men. Future studies are needed to elucidate the causal associations of TB and GGT with CVD.

Tapping the Power of Plasma Lipidome to Improve Hypertriglyceridemic Waist as a Predictor of Future Type 2 Diabetes

Hypertriglyceridemic waist is considered a specific predictor of T2D because it combines the predictive value of waist circumference (WC) and serum triglycerides (TG). Our objective was to investigate if the addition of specific triacylglycerol (TAG) lipid species to WC performs better than the combination of WC and TG to predict future T2D in initially diabetes‐free individuals (n=771, 9197 person‐years follow‐up). The participants were from the San Antonio Family Heart Study and the plasma lipidome was quantified using high‐performance liquid chromatography and mass spectrometry. A forward addition approach to optimize the integrated discrimination index (IDI) identified five independent and significant TAG species out of 43 species investigated. Selection of TAG species using stepwise forward added IDI Association of TAG species with T2D Step TAG Retained IDI p Scale Coefficient p 1 TAG 16:0/16:0/18:2 0.0278 0.0031 10‐4 0.6915 0.0004 2 TAG 14:1/18:1/18:1 0.0264 8.9x10‐5 10‐3 ‐0.4125 0.0003 3 TAG 18:0/18:2/18:2 0.0025 0.0391 10‐3 ‐0.2426 0.0278 4 TAG 16:0/18:1/18:1 0.0075 0.0224 10‐5 1.1917 0.0105 5 TAG 14:0/18:2/18:2 0.0070 0.0209 10‐3 0.5095 0.0308 A summary TAG score was constructed from these five TAG species based on logistic regression model as shown in Table 1. Comparison of the predictive performance of the TAG score with that of TG concentration demonstrated the additive value of the TAG score but not of TG to basic clinical predictors of T2D including prediabetes. Statistic Base Model Estimate (p) Base Model + Prediabetes Estimate (p) ΔAROC TAG Score 0.0374 (0.0063) 0.0274 (0.0014) IDI TAG Score 0.0726 (5.3x10‐7) 0.0585 (9.9x10‐6) NRI TAG Score 0.6008 (5.7x10‐10) 0.5937 (8.9x10‐10) ΔAROC TG 0.0035 (0.4472) 0.0014 (0.6156) IDI TG 0.0059 (0.0407) 0.0011 (0.2827) NRI TG 0.3500 (0.0002) 0.1553 (0.0578) Our results provide two interesting implications: first, not all TAG species are similar (either in strength or direction of association) with regards their predictive value for future T2D; and second, few TAG species from the plasma lipidome can be combined with WC to significantly improve the prediction of future T2D.This work was supported in part by NIH grants, AT&amp;T Foundation anad facilities supported by NIH grants.

Common carotid artery end-diastolic velocity is independently associated with future cardiovascular events.

Carotid ultrasound is widely used to measure haemodynamic parameters, such as intima-media thickness and blood flow velocities (i.e. peak-systolic velocity [PSV], end-diastolic velocity [EDV], and resistive index [RI]). However, the association between blood flow velocities and cardiovascular events remains unclear. Baseline data, including quantitative ultrasonography, were obtained from 3146 adults as part of the Cardiovascular Diseases Risk Factor Two-Township Study. Occurrence of ischaemic heart disease (IHD) and stroke was determined from insurance claims and death certificates. The hazard ratio (HR) of CVD (IHD and stroke combined) was calculated for EDV and PSV of the common carotid artery using Cox models. Net reclassification index and integrated discrimination index were used to evaluate the capacity of EDV to predict IHD, stroke, and CVD. Median follow-up was 12.8 years. There were 220 cases of IHD and 247 cases of stroke. The HR (95% CI) for CVD from univariate analysis was 4.54 (3.51-5.85) for EDV <15 cm/s relative to EDV ≥ 20 cm/s (p < 0.0001), and 3.23 (2.51-4.15) for PSV < 65 cm/s relative to PSV ≥ 80 cm/s (p < 0.0001). The HR (95% CI) for CVD from multivariate analysis was 1.66 (1.22-2.26) for EDV < 15 cm/s relative to EDV ≥ 20 cm/s, and 1.39 (1.03-1.89) for PSV < 65 cm/s relative to PSV ≥ 80 cm/s. EDV slightly but significantly improved prediction of CVD (integrated discrimination index 0.56%, p = 0.016). Low common carotid EDV and PSV were independently associated with future CVD, and EDV improved the prediction of future CVD. More prospective studies are required in different ethnic groups to understand the significance and implication of these findings.

Inflammatory phenotype of circulating endothelial-derived microparticles in chronic heart failure patients with metabolic syndrome

Metabolic syndrome (MetS) may have an adverse impact on cardiovascular events in unselected populations. However, the role of MetS in chronic heart failure (CHF) subjects remains controversial. Endothelial-derived microparticles (EMPs) may play a pivotal role in cell-to-cell cooperation, effects negatively on tissue reparation, and mediates vascular function. Pattern of circulating EMPs probably reflects imbalance between endothelial cell injury and endothelial repair. The aim of the study: to investigate an inflammatory pattern of circulating EMPs in MetS patients with CHF. Methods: The study retrospectively evolved 101 patients with MetS (54 subjects with CHF and 47 patients without CHF) without documented coronary artery stenosis > 50% at least of one artery and 35 healthy volunteers. Biomarkers were measured at baseline of the study. Circulating EMPs were phenotyped by flow cytometry technique. Results: We found CD62E+ EMPs and CD62E+ to CD31+/annexin V+ ratio were elevated in healthy persons when compared with MetS patients. CD62E+ to CD31+/annexin V+ ratio was found to be higher in the MetS patients without CHF compared with MetS patients with CHF. Using multiple linear regression analysis, independent impact of BMI, NT-proBNP, osteoprotegerin and hs-CRP on decreased CD62E+ to CD31+/annexin V+ ratio was found. We found that adding of combination of inflammatory biomarkers (hs-CRP, osteoprotegerin and NT-proBNP) to the based model (BMI) improved the relative integrated discrimination indices by 11.4% for decreased CD62E+ to CD31+/annexin V+ ratio. In conclusion, we found that biomarkers of biomechanical stress (NT-proBNP) and inflammation (hs-CRP, osteoprotegerin) remain statistically significant predictors for decreased CD62E+ to CD31+/annexin V+ ratio in MetS patients with CHF.

Immune Phenotypes of Endothelial-Derived Microparticles in Dysmetabolic Patients.

Type two diabetes mellitus remains a leading contributor to cardiovascular mortality worldwide. This study was conducted to investigate the pattern of circulating endothelial-derived microparticles in diabetes patients in comparison with metabolic syndrome subjects. Methods: The study retrospectively evolved 101 patients (54 subjects with type two diabetes mellitus and 47 patients with metabolic syndrome) and 35 healthy volunteers. All the patients have given written informed consent for participation in the study. Biomarkers were measured at baseline of the study. Results: There is a significant difference between healthy subjects and patients regarding CD31+/annexin V+ to CD62E+ ratio of endothelial-derived microparticle, which reflects impaired phenotype of microparticles. Therefore, CD31+/annexin V+ to CD62E+ ratio was found to be higher in the type two diabetes mellitus patients compared to metabolic syndrome patients. Using multivariate linear regression analyses, independent impact of type two diabetes mellitus (r=0.40, P=0.003), OPG (r=0.37, P=0.001), hs-CRP (r=0.347, P=0.001), and adiponectin (r=0.33, P=0.001) on increased CD31+/annexin V+ to CD62E+ ratio of endothelial-derived microparticles was determined. Using C-statistics we found that inflammatory biomarkers (hs-C reactive protein, osteoprotegerin and adiponectin) added to the based model (type two diabetes mellitus) improved the relative integrated discrimination indices by 12.6% for increased CD31+/annexin V+ to CD62E+ ratio. In conclusion, we found that patients with type two diabetes mellitus and metabolic syndrome may distinguish predominantly appeared phenotypes of circulating endothelial-derived microparticles associated with pro-inflammatory cytokine over production. Elevated CD31+/annexin V+ to CD62E+ ratio is indicator of impaired immune phenotype of endothelial-derived microparticles, which allows determining pattern of microparticles in dysmetabolic disorder patients.

Improved Reclassification of Mortality Risk by Assessment of Physical Activity in Patients Referred for Exercise Testing

BackgroundInability to meet minimal guidelines on physical activity is associated with poor health outcomes, but quantifying activity can be complex. We studied whether a simple question regarding participation in regular activity improves risk classification for all-cause mortality. MethodsMaximal exercise testing was performed in 6962 patients (mean age, 58.9 ± 11 years) for clinical reasons. Subjects also were assessed for participation in regular activity using a simple yes/no response to meeting minimal recommendations on activity. The incremental value of adding a simple physical activity assessment to clinical, demographic, and exercise test information to predict mortality was determined using Cox proportional hazards models, net reclassification improvement, and integrated discrimination index during a mean follow-up of 9.7 ± 4 years. ResultsSubjects who did not meet the minimal guidelines on activity had a lower exercise capacity (7.4 ± 4.3 vs 9.1 ± 3.6 metabolic equivalents, P < .0001) and a higher annual mortality rate (2.42% vs 1.71%, P < .001). Not meeting activity guidelines was associated with an age-adjusted 36% higher risk of mortality (hazard ratio, 1.36; 95% confidence interval, 1.22-1.51, P < .0001). Among clinical and exercise test variables, fitness had the highest C-index for predicting mortality (0.72, P < .001). The addition of physical activity classification to a model including traditional risk factors resulted in a net reclassification improvement of 22.8% (P < .001); adding fitness to the traditional risk factor model resulted in a net reclassification improvement of 43.5% (P < .001). ConclusionsThe addition of a simple assessment of physical activity status significantly improves reclassification of risk for all-cause mortality among patients who are referred for exercise testing.

Left Ventricular Mass and the Risk of Sudden Cardiac Death: A Population‐Based Study

BackgroundLeft ventricular (LV) mass ascertained using echocardiography may enhance risk stratification for sudden cardiac death. The objective of this study was to assess the association between left ventricular mass and the risk of sudden cardiac death in a population‐based cohort and determine its incremental value beyond conventional risk predictors.Methods and ResultsAssessment of LV mass was based on echocardiography in a sample of 905 middle‐aged men representative of the general population (aged 42 to 61 years). During the follow‐up period of 20 years, there were a total of 63 sudden cardiac deaths. In a comparison of the top versus the bottom quartile of LV mass adjusted by body surface area (>120 versus <89 g/m2), the multivariable adjusted hazard ratio was 2.57 (95% CI 1.24 to 5.31, P=0.010). Further adjustment for LV function only modestly attenuated the risk of sudden cardiac death among men with LV mass of >120 g/m2 (hazard ratio 2.29, 95% CI 1.10 to 4.74, P=0.026). Addition of LV mass adjusted by body surface area to a conventional risk factor model for sudden cardiac death improved the integrated discrimination index by 0.033 (95% CI 0.009 to 0.057, P=0.007) and the category‐free net reclassification index by 0.501 (95% CI 0.092 to 0.911, P=0.016).ConclusionsIndexed LV mass by body surface area is an independent predictor of sudden cardiac death and may help improve the risk prediction of sudden cardiac death beyond conventional cardiovascular risk factors.

The association of CHA2DS2-VASc score and blood biomarkers with ischemic stroke outcomes: the Belgrade stroke study.

BackgroundMany blood biomarkers have a positive association with stroke outcome, but adding blood biomarkers to the National Institutes of Health Stroke Scale (NIHSS) did not significantly improve its discriminatory ability. We investigated the association of the CHA2DS2-VASc score with unfavourable functional outcome (defined as a 30-day modified Rankin Scale [mRS] ≥3) in patients presenting with acute ischemic stroke (AIS), and examined whether the addition of blood biomarkers (troponin I [TnI], fibrinogen, C-reactive protein [CRP]) affects the model discriminatory ability.MethodsWe conducted an observational single-centre study of consecutive patients with AIS. All patients were admitted to hospital within 24 hours from the neurological symptoms onset.ResultsOf 240 patients (mean age 70.0±8.9 years), unfavourable 30-day outcome occurred in 92 (38.3%). Patients with mRS≥3 were older and more likely to have atrial fibrillation or other comorbidities (all p<0.001). They had higher levels of CRP, fibrinogen, TnI and higher CHA2DS2-VASc and CHADS2 scores (all p<0.05). The adjusted CHA2DS2-VASc score had excellent predictive ability for poor stroke outcome (c-statistic 0.982;95%CI,0.964–1.000, p<0.001). Whilst CRP had the highest sensitivity (83.7%), cardiac TnI was the most specific (97.3%) for prediction of poor stroke outcome (cut-off: >0.09µg/L). Compared with each of these biomarkers, CHA2DS2-VASc score had significantly better predictive ability for poor stroke outcome (c-statistic for CRP, Fibrinogen and TnI was 0.853;95%CI,0.802–0.895, 0.848;95%CI,0.796–0.891, and 0.792;95%CI,0.736–0.842, all p<0.001, respectively, versus 0.932;95%CI,0.892–0.960, p<0.001 for the CHA2DS2-VASc, all p for the comparisons<0.01). There was no significant difference in the predictive ability of the CHA2DS2-VASc score vs. combinations of the CHA2DS2-VASc and TnI or TnI, fibrinogen and CRP (z statistic 0.369, p = 0.7119; integrated discrimination index 0.00801 and 0.00172, respectively, both p>0.05).ConclusionsThe CHA2DS2-VASc score alone reliably predicts 30-day unfavourable outcome of stroke. Adding blood biomarkers to the CHA2DS2-VASc score did not significantly increase the predictive ability of the model.

Plasma triglycerides predict incident albuminuria and progression of coronary artery calcification in adults with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes Study.

Coronary artery disease and diabetic nephropathy, which are thought to share pathogenic mechanisms, remain the most common causes of mortality in type 1 diabetes (T1D). Data from basic and clinical studies indicate that hypertriglyceridemia plays an important role in the pathogenesis of vascular complications, but the role of triglycerides (TG) in the normal range remains unresolved in T1D. We hypothesized that fasting TG would independently predict cardiorenal disease in adults with T1D and normal-to-low levels of TG. Subjects (N = 652) were 19 to 56 years old at baseline and reexamined 6 years later. Urinary albumin excretion was measured, and categorized as microalbuminuria or greater. Progression of coronary artery calcification (CACp), measured using electron beam computed tomography, was defined as a change in the square root transformed CAC volume ≥2.5. The association of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, non-HDL-C, natural log triglyceride (lnTG), ln(TG/HDL-C) ratio with CACp and incident albuminuria were examined in logistic regression. The models were adjusted for age, sex, T1D duration, hemoglobin A1c, systolic blood pressure, diastolic blood pressure, blood pressure medications, statins, and smoking status. Integrated discrimination index and net reclassification improvement were used to examine prediction performance. Incident albuminuria was independently associated with CACp. lnTG independently predicted both incident albuminuria (odds ratio: 1.53, 1.02-2.30, P = .04) and CACp (1.41, 1.11-1.80, P = .006). The addition of lnTG to ABC risk factors (HbA1c, systolic blood pressure, diastolic blood pressure, and LDL-C) moderately improved discrimination and reclassification of CACp and incident albuminuria. In adults with T1D, fasting TG independently predicted cardiorenal disease over 6 years and improved reclassification of risk by conventional risk factors.

Predictive value of apoptotic microparticles to mononuclear progenitor cells ratio in advanced chronic heart failure patients

BackgroundAcutely decompensated chronic heart failure (ADHF) is considered a life-threatening event. Despite contemporary treatment strategies of ADHF, frequent recurrent hospitalizations due to other cardiovascular reasons after discharge of patients from hospital occur. The objective of the study was to examine the prognostic value of circulating endothelial-derived apoptotic microparticles (EMPs) to mononuclear progenitor cells (MPCs) ratio for post-discharge patients with clinical stabilization after ischemic ADHF. MethodsWe consecutively enrolled 136 patients (62 male) with coronary artery disease (CAD) admitted with a primary diagnosis of ADHF. All patients gave written informed consent for participation in the study. At baseline, all enrolled patients were hemodynamically stable and they had New York Heart Association (NYHA) III/IV classes of ischemic chronic heart failure (CHF). Observation period started at discharge from the hospital and was up to 3 years. Flow cytometry analysis for quantifying the number of EMPs and angiogenic MPCs was used. ResultsCalculated EMP to MPC ratios in survivor and dead patient cohort were 8.4 (95% CI=7.6–9.2) and 78.9 (95% CI=53.0–116.6), respectively (p=0.001). MPCs, EMPs, NYHA class, N-terminal pro-brain natriuretic peptide (NT-proBNP) and increased NT-proBNP>30% within 24–84h of admission period remained statistically significant for all-cause mortality, CHF-related death, and CHF-related rehospitalization, whereas left ventricular ejection fraction and high-sensitivity C-reactive protein for all variables did not. We found that the addition of EPMs to MPCs ratio to the ABC model (NT-pro-BNP, increased NT-pro-BNP>30%) improved the relative integrated discrimination indices by 19.6% for all-cause mortality, by 21.7% for CHF-related death, and by 19.5% for CHF-related rehospitalization. ConclusionWe demonstrated that EMP to MPC ratio is considered an important indicator of an imbalance between angiogenic and apoptotic responses with possible relation to cardiovascular outcomes in post-discharge patients with clinical stabilization after ischemic ADHF.

Risk score to predict hospital-acquired pneumonia after spontaneous intracerebral hemorrhage.

We aimed to develop a risk score (intracerebral hemorrhage-associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer-Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively. A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0.72-0.77) and validation (AUROC, 0.76; 95% confidence interval, 0.71-0.79) cohorts. The ICH-APS-A was more sensitive for patients with length of stay >48 hours (AUROC, 0.78; 95% confidence interval, 0.75-0.81) than those with length of stay <48 hours (AUROC, 0.64; 95% confidence interval, 0.55-0.73). The ICH-APS-A was well calibrated (Hosmer-Lemeshow test) in the derivation (P=0.20) and validation (P=0.66) cohorts. Similarly, a 26-point ICH-APS-B was established. The ICH-APS-A and ICH-APS-B were not significantly different in discrimination and reclassification for SAP after ICH. The ICH-APSs are valid risk scores for predicting SAP after ICH, especially for patients with length of stay >48 hours.

Predicting Long-Term Cardiovascular Risk Using the Mayo Clinic Cardiovascular Risk Score in a Referral Population

Exercise testing provides valuable information but is rarely integrated to derive a risk prediction model in a referral population. In this study, we assessed the predictive value of conventional cardiovascular risk factors and exercise test parameters in 6,546 consecutive adults referred for exercise testing, who were followed for a period of 8.1 ± 3.7years for incident myocardial infarction, coronary revascularization, and cardiovascular death. A risk prediction model was developed, and cross-validation of model was performed by splitting the data set into 10 equal random subsets, with model fitting based on 9 of the 10 subsets and testing in of the remaining subset, repeated in all 10 possible ways. The best performing model was chosen based on measurements of model discrimination and stability. A risk score was constructed from the final model, with points assigned for the presence of each predictor based on the regression coefficients. Using both conventional risk factors and exercise test parameters, a total of 9 variables were identified as independent and robust predictors and were included in a risk score. The prognostic ability of this model was compared with that of the Adult Treatment Panel III model using the net reclassification and integrated discrimination index. From the cross-validation results, the c statistic of 0.77 for the final model indicated strong predictive power. In conclusion, we developed, tested, and internally validated a novel risk prediction model using exercise treadmill testing parameters.

Association of heart-type fatty acid-binding protein with cardiovascular risk factors and all-cause mortality in the general population: the Takahata study.

BackgroundDespite many recent advances in medicine, preventing the development of cardiovascular diseases remains a challenge. Heart-type fatty acid-binding protein (H-FABP) is a marker of ongoing myocardial damage and has been reported to be a useful indicator for future cardiovascular events. However, it remains to be determined whether H-FABP can predict all-cause and cardiovascular deaths in the general population.Methods and ResultsThis longitudinal cohort study included 3,503 subjects who participated in a community-based health checkup with a 7-year follow-up. Serum H-FABP was measured in registered subjects. The results demonstrated that higher H-FABP levels were associated with increasing numbers of cardiovascular risk factors, including hypertension, diabetes mellitus, obesity, and metabolic syndrome. There were 158 deaths during the follow-up period, including 50 cardiovascular deaths. Deceased subjects had higher H-FABP levels compared to surviving subjects. Multivariate Cox proportional hazard regression analysis revealed that H-FABP is an independent predictor of all-cause and cardiovascular deaths after adjustments for confounding factors. Subjects were divided into four quartiles according to H-FABP level, and Kaplan-Meier analysis demonstrated that the highest H-FABP quartile was associated with the greatest risks for all-cause and cardiovascular deaths. Net reclassification index and integrated discrimination index were significantly increased by addition of H-FABP to cardiovascular risk factors.ConclusionsH-FABP level was increased in association with greater numbers of cardiovascular risk factors and was an independent risk factor for all-cause and cardiovascular deaths. H-FABP could be a useful indicator for the early identification of high-risk subjects in the general population.

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus

Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria. Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index. In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes. Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.