Regional extracellular volume within late gadolinium enhancement-positive myocardium to differentiate cardiac sarcoidosis from myocarditis of other etiology: a cardiovascular magnetic resonance study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a pivotal role in diagnosing myocardial inflammation. In addition to late gadolinium enhancement (LGE), native T1 and T2 mapping as well as extracellular volume (ECV) are essential tools for tissue characterization. However, the differentiation of cardiac sarcoidosis (CS) from myocarditis of other etiology can be challenging. Positron-emission tomography-computed tomography (PET-CT) regularly shows the highest Fluordesoxyglucose (FDG) uptake in LGE positive regions. It was therefore the aim of this study to investigate, whether native T1, T2, and ECV measurements within LGE regions can improve the differentiation of CS and myocarditis compared with using global native T1, T2, and ECV values alone. METHODS: PET/CT confirmed CS patients and myocarditis patients (both acute and chronic) from a prospective registry were compared with respect to regional native T1, T2, and ECV. Acute and chronic myocarditis were defined based on the 2013 European Society of Cardiology position paper on myocarditis. All parametric measures and ECV were acquired in standard fashion on three short-axis slices according to the ConSept study for global values and within PET-CT positive regions of LGE. RESULTS: Between 2017 and 2020, 33 patients with CS and 73 chronic and 35 acute myocarditis patients were identified. The mean ECV (± SD) in LGE regions of CS patients was higher than in myocarditis patients (CS vs. acute and chronic, respectively: 0.65 ± 0.12 vs. 0.45 ± 0.13 and 0.47 ± 0.1; p < 0.001). Acute and chronic myocarditis patients had higher global native T1 values (1157 ± 54 ms vs. 1196 ± 63 ms vs. 1215 ± 74 ms; p = 0.001). There was no difference in global T2 and ECV values between CS and acute or chronic myocarditis patients. CONCLUSION: This is the first study to show that the calculation of regional ECV within LGE-positive regions may help to differentiate CS from myocarditis. Further studies are warranted to corroborate these findings.

Definition of acute kidney injury impacts prevalence and prognosis in ACS patients undergoing coronary angiography.

BACKGROUND: Development of acute kidney injury (AKI) in invasively managed patients with acute coronary syndrome (ACS) is associated with a markedly increased mortality risk. Different definitions of AKI are in use, leading to varying prevalence and outcome measurements. The aim of the present study is to analyze an ACS population undergoing coronary angiography for differences in AKI prevalence and outcome using four established AKI definitions. METHODS: 944 patients (30% female) were enrolled in a prospective registry between 2003 and 2005 with 6-month all-cause mortality as outcome measure. Four established AKI definitions were used: an increase in serum creatinine (sCR) ≥ 1.5 fold, ≥ 0.3 mg/dl, and ≥ 0.5 mg/dl and a decrease in eGFR > 25% from baseline (AKIN 1, AKIN 2, CIN, and RIFLE definition groups, respectively). RESULTS: AKI rates varied widely between the different groups. Using the CIN definition, AKI frequency was lowest (4.4%), whereas it was highest if the RIFLE definition was applied (13.2%). AKIN 2 displayed a twofold higher AKI prevalence compared with AKIN 1 (10.2% vs. 5.3% (p < 0.001)). AKI was a strong risk factor for mid-term mortality, with distinctive variability between the definitions. The lowest mortality risk was found in the RIFLE group (HR 6.0; 95% CI 3.7-10.0; p < 0.001), whereas CIN revealed the highest risk (HR 16.7; 95% CI 9.9-28.1; p < 0.001). CONCLUSION: Prevalence and outcome in ACS patients varied considerably depending on the AKI definition applied. To define patients with highest renal function-associated mortality risk, use of the CIN definition seems to have the highest prognostic relevance.

The adipokine fatty-acid binding protein 4 and cardiac remodeling.

BACKGROUND: Previous publications about the association between fatty-acid binding protein 4 (FABP4) and cardiac remodeling have reported different, both beneficial and harmful, associations. Aim of the present investigation was to evaluate the association of FABP4 with parameters of myocardial remodeling defined by cardiac magnetic resonance imaging (CMR). METHODS: We investigated plasma FABP4 levels in 331 patients (71% men, mean age 63±13 years) with preserved left ventricular ejection fraction (LVEF ≥ 55%) who underwent a CMR examination. We used linear cox regression to investigate associations between FABP4 and left ventricular end-diastolic diameter (LVEDD), right ventricular end-diastolic diameter (RVEDD), relative wall thickness (RWT), left ventricular mass index (LVMI), and LVEF (unadjusted and adjusted for age, sex, body mass index, cardiac biomarkers, and comorbidities). RESULTS: FABP4 levels were associated with lower LVMI and higher NT-proBNP levels in an adjusted model. The inverse association between FABP4 and LVMI was more pronounced in lower FABP4 levels, whereas the positive association between FABP4 and NT-proBNP was more pronounced in relatively high NT-proBNP levels. CONCLUSIONS: Possible beneficial and harmful associations between FABP4 and left ventricular size have been reported. Our results suggest a beneficial association with LVMI (more pronounced in lower FABP4 levels) but a harmful association with NT-proBNP (more pronounced in higher FABP4 levels). Therefore, our results might indicate a potential dose-dependent association of FABP4, but this observation needs further investigation in larger study samples.

Identification of acute myocardial infarction in elderly patients using optimized highly sensitive troponin I thresholds.

Purpose: Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs. Material and methods: Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients > 70 years were classified as elderly. hs-cTnI was measured upon admission. Results: Around 34.7% of 2903 patients were classified as elderly. Around 22.5% of elderly patients were finally diagnosed with AMI. Elderly patients had higher hs-cTnI levels at admission irrespective of the final diagnosis (p < 0.001). According to the AUROC, hs-cTnI was a strong marker for detection of AMI in elderly patients. Application of the 99th percentile cutoffs showed a substantially lower specificity in elderly. By using optimized thresholds, specificity was improved to levels as in younger patients in both cohorts but accompanied with a decrease in sensitivity. Conclusions: hs-cTnI levels have a lower specificity for detecting AMI in elderly patients. This lower specificity can be improved by using hs-cTnI thresholds optimized for elderly patients.

Estimation of Values below the Limit of Detection of a Contemporary Sensitive Troponin I Assay Improves Diagnosis of Acute Myocardial Infarction.

BACKGROUND: The limit of detection (LoD) is the minimal amount of a substance that can be consistently detected. In the diagnosis of acute myocardial infarction (AMI) many patients present with troponin concentrations below the LoD of contemporary sensitive cardiac troponin I (cs-cTnI) assays. These censored values below the LoD influence the diagnostic performance of these assays compared to highly sensitive cTnI (hs-cTnI) assays. Therefore we assessed the impact of a new approach for interpolation of the left-censored data of a cs-cTnI assay in the evaluation of patients with suspected AMI. METHODS: Our posthoc analysis used a real world cohort of 1818 patients with suspected MI. Data on cs-cTnI was available in 1786 patients. As a comparator the hs-cTnI version of the assay was used. To reconstruct quantities below the LoD of the cs-cTnI assay, a gamma regression approach incorporating the GRACE (Global Registry of Acute Coronary Events) score variables was used. RESULTS: Censoring of cs-cTnI data below the LoD yielded weaker diagnostic information [area under the curve (AUC), 0.781; 95% CI, 0.731-0.831] regarding AMI compared to the hs-cTnI assay (AUC, 0.949; CI, 0.936-0.961). Use of our model to estimate cs-cTnI values below the LoD showed an AUC improvement to 0.921 (CI, 0.902-0.940). The cs-cTnI LoD concentration had a negative predictive value (NPV) of 0.950. An estimated concentration that was to be undercut by 25% of patients presenting with suspected AMI was associated with an improvement of the NPV to 0.979. CONCLUSIONS: Estimation of values below the LoD of a cs-cTnI assay with this new approach improves the diagnostic performance in evaluation of patients with suspected AMI.

A 1-year cross-sectional analysis of non-interventional post-marketing study protocols submitted to the German Federal Institute for Drugs and Medical Devices (BfArM).

PURPOSE: The aim of non-interventional studies (NIS) with medicinal products is to investigate the use of authorized medicinal products in daily routine. In the past, this type of study has been subject to frequent criticism, and many recommendations have been published. The aim of our study was to assess the quality of NIS study protocols. METHODS: Nearly all NIS study protocols submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) within a period of one year could be analyzed. The protocols were evaluated in terms of objectives, methods and included patients, as well as with regard to their compliance with quality recommendations for NIS by federal authorities and pharmaceutical industry associations. RESULTS: The 136 NIS available for study were scheduled to enroll approximately 330,000 patients (2,500 patients per study) and 43,000 healthcare professionals. Of these NIS, 58 % were performed with medicinal products that had been authorized within the past 5 years; however, 68 % of the investigated active pharmaceutical ingredients were older than 5 years, and 19 % were even older than 19 years. Only 56 % of the protocols provided information on publication policy, and 65 % required the involvement of ethic committees. The adherence to current quality recommendations was average, but the compliance of NIS performed by member companies of the Association of Research-Based Pharmaceutical Companies was significantly higher than that of other sponsors. CONCLUSIONS: Current quality recommendations are still not fully implemented in most NIS protocols. Therefore, the scientific value of many NIS is still questionable, and the criticism that NIS are mainly conducted for marketing reasons could not be refuted by the data analyzed here.

Native T2 Predicts Myocardial Inflammation Irrespective of a Patient's Volume Status.

Myocardial inflammation and edema are major pathological features in myocarditis. Myocardial tissue water content and myocardial edema can be quantified via T2 mapping. Thus, cardiac magnetic resonance (CMR) is the noninvasive gold standard for diagnosing myocarditis. Several studies showed an impact of short-term volume changes on T2 relaxation time. Plasma volume status (PVS) is a good surrogate parameter to quantify a patient's volume status, and it is simple to use. The aim of this study was to determine the effect of PVS on the diagnostic value of T2 relaxation time in myocardial inflammation. Between April 2017 and December 2022, patients who were indicated for cardiac CMR were included in our prospective clinical registry. Patients with myocardial inflammation and those with unremarkable findings were analyzed in the present study. A blood sample was drawn, and PVS was calculated. Patients were separated into PVS tertiles to explore a possible nonlinear dose-response relationship. Logistic regression analysis was used to determine whether T2 is an independent predictor of myocardial inflammation. A total of 700 patients (47.43% female) were eligible for analysis. Of these, 551 patients were healthy (78.7%), while 149 (21.3%) showed signs of myocardial inflammation. The T2 relaxation time was elevated in patients with myocardial inflammation (40 ms [IQR 37-42 ms] vs. 38.0 ms [IQR 36-39 ms], p < 0.001). PVS showed no difference between the groups (-12.94 [IQR -18.4--7.28] vs.-12.19 [IQR -18.93--5.87], p = 0.384). T2 showed a clear dose-response relationship with PVS, with increasing T2 values along the PVS tertiles. In spite of this, T2 was found to be an independent marker of myocardial inflammation in logistic regression (OR T2 1.3 [95% CI 1.21-1.39], p < 0.001), even after adjusting for PVS (OR T2 [adj. PVS] 1.31 [95% CI 1.22-1.40], p < 0.001). Despite a dose-response relationship between T2 and the volume status, T2 was found to be an independent indicator of myocardial inflammation.

Circulating Monocyte Subsets Are Associated With Extent of Myocardial Injury but Not With Type of Myocardial Infarction.

Inflammation is a hallmark of the period after a myocardial infarction (MI) that is either promoted or resolved by distinct subtypes of circulating inflammatory cells. The three main monocyte subpopulations play different roles inflammation. This study examined whether the type of MI (type 1 or type 2) or the extent of myocardial injury is associated with differences in monocyte subpopulations. For this purpose, peripheral whole blood from patients with a suspected MI was used for flow cytometric measurements of the monocyte subpopulations, and myocardial injury was classified by cardiac troponin levels in serum. In patients with acute coronary syndrome (n = 82, 62.2% male) similar proportions of the monocyte subsets were associated with the two types of MI, whereas total monocyte counts were increased in patients with substantial myocardial injury vs. those with minor injury (p = 0.045). This was accompanied by a higher proportion of intermediate (p = 0.045) and classical monocytes (p = 0.059); no difference was found for non-classical monocytes (p = 0.772). In patients with chronic coronary syndrome (n = 144, 66.5% male), an independent association with myocardial injury was also observed for classical monocytes (p = 0.01) and intermediate monocytes (p = 0.08). In conclusion, changes in monocyte subpopulation counts, particularly for classical and intermediate monocytes, were related to the extent of myocardial injury in acute and stable coronary artery disease but not to the type of MI.

CMR-derived myocardial strain analysis differentiates ischemic and dilated cardiomyopathy-a propensity score-matched study.

Left ventricular (LV) longitudinal, circumferential, and radial motion can be measured using feature tracking of cardiac magnetic resonance (CMR) images. The aim of our study was to detect differences in LV mechanics between patients with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) who were matched using a propensity score-based model. Between April 2017 and October 2019, 1224 patients were included in our CMR registry, among them 141 with ICM and 77 with DCM. Propensity score matching was used to pair patients based on their indexed end-diastolic volume (EDVi), ejection fraction (EF), and septal T1 relaxation time (psmatch2 module L Feature tracking provided six parameters for global longitudinal, circumferential, and radial strain with corresponding strain rates in each group. Strain parameters were compared between matched pairs of ICM and DCM patients using paired t tests. Propensity score matching yielded 72 patients in each group (DCM mean age 58.6 ± 11.6 years, 15 females; ICM mean age 62.6 ± 13.2 years, 11 females, p = 0.084 and 0.44 respectively; LV-EF 32.2 ± 13.5% vs. 33.8 ± 12.1%, p = 0.356; EDVi 127.2 ± 30.7 ml/m2 vs. 121.1 ± 41.8 ml/m2, p = 0.251; native T1 values 1165 ± 58 ms vs. 1167 ± 70 ms, p = 0.862). There was no difference in global longitudinal strain between DCM and ICM patients (- 10.9 ± 5.5% vs. - 11.2 ± 4.7%, p = 0.72), whereas in DCM patients there was a significant reduction in global circumferential strain (- 10.0 ± 4.5% vs. - 12.2 ± 4.7%, p = 0.002) and radial strain (17.1 ± 8.51 vs. 21.2 ± 9.7%, p = 0.039). Our data suggest that ICM and DCM patients have inherently different myocardial mechanics, even if phenotypes are similar. Our data show that GCS is significantly more impaired in DCM patients. This feature may help in more thoroughly characterizing cardiomyopathy patients.

Application and Validation of the Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio in Patients with Ischemic and Non-Ischemic Cardiomyopathy.

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (<0.38 mm/mmHg) and TAPSE (<16 mm) were associated with a lower RVEF and a long-axis RV global longitudinal strain (GLS) as well as higher RVESVI, RVEDVI and NT-proBNP. A low TAPSE/PASP, but not TAPSE, was associated with a lower LVEF and long-axis LV GLS, and a higher LVESVI, LVEDVI and T1 relaxation time at the interventricular septum and the RV insertion points. Furthermore, in the validation cohort, low TAPSE/PASP was associated with a higher mortality and TAPSE/PASP was an independent predictor of mortality. TAPSE/PASP is a predictor of maladaptive RV and LV remodeling associated with poor outcomes in cardiomyopathy patients.

Joint influences of obesity, diabetes, and hypertension on indices of ventricular remodeling: Findings from the community-based Framingham Heart Study.

INTRODUCTION: Obesity, hypertension, and diabetes are independently associated with cardiac remodeling and frequently co-cluster. The conjoint and separate influences of these conditions on cardiac remodeling have not been investigated. MATERIALS AND METHODS: We evaluated 5,741 Framingham Study participants (mean age 50 years, 55% women) who underwent echocardiographic measurements of left ventricular (LV) mass (LVM), LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral E/e', left atrial end-systolic (peak) dimension (LASD) and emptying fraction (LAEF). We used multivariable generalized linear models to estimate the adjusted-least square means of these measures according to cross-classified categories of body mass index (BMI; normal, overweight and obese), hypertension (yes/no), and diabetes (yes/no). RESULTS: We observed statistically significant interactions of BMI category, hypertension, and diabetes with LVM, LVEF, GLS, and LAEF (p for all 3-way interactions <0.01). Overweight and obesity (compared to normal BMI), hypertension, and diabetes status were individually and conjointly associated with higher LVM and worse GLS (p<0.01 for all). We observed an increase of 34% for LVM and of 9% for GLS between individuals with a normal BMI and without hypertension or diabetes compared to obese individuals with hypertension and diabetes. Presence of hypertension was associated with higher LVEF, whereas people with diabetes had lower LVEF. CONCLUSIONS: Obesity, hypertension, and diabetes interact synergistically to influence cardiac remodeling. These findings may explain the markedly heightened risk of heart failure and cardiovascular disease when these factors co-cluster.

Identifying Heart Failure in ECG Data With Artificial Intelligence-A Meta-Analysis.

Introduction: Electrocardiography (ECG) is a quick and easily accessible method for diagnosis and screening of cardiovascular diseases including heart failure (HF). Artificial intelligence (AI) can be used for semi-automated ECG analysis. The aim of this evaluation was to provide an overview of AI use in HF detection from ECG signals and to perform a meta-analysis of available studies. Methods and Results: An independent comprehensive search of the PubMed and Google Scholar database was conducted for articles dealing with the ability of AI to predict HF based on ECG signals. Only original articles published in peer-reviewed journals were considered. A total of five reports including 57,027 patients and 579,134 ECG datasets were identified including two sets of patient-level data and three with ECG-based datasets. The AI-processed ECG data yielded areas under the receiver operator characteristics curves between 0.92 and 0.99 to identify HF with higher values in ECG-based datasets. Applying a random-effects model, an sROC of 0.987 was calculated. Using the contingency tables led to diagnostic odds ratios ranging from 3.44 [95% confidence interval (CI) = 3.12-3.76] to 13.61 (95% CI = 13.14-14.08) also with lower values in patient-level datasets. The meta-analysis diagnostic odds ratio was 7.59 (95% CI = 5.85-9.34). Conclusions: The present meta-analysis confirms the ability of AI to predict HF from standard 12-lead ECG signals underlining the potential of such an approach. The observed overestimation of the diagnostic ability in artificial ECG databases compared to patient-level data stipulate the need for robust prospective studies.

Prognostic Significance of Echocardiographic Measures of Cardiac Remodeling.

BACKGROUND: In recent decades, novel echocardiographic measures have constantly emerged. It is still unclear which echocardiographic measures have the most significant prognostic value in the general population. Accordingly, the aim of this study was to compare the prognostic value of a large panel of echocardiographic measures to identify the most promising measures. METHODS: A total of 1,497 Framingham study participants (mean age, 65 years; 55.4% women) who underwent echocardiographic measurements of left ventricular ejection fraction, left ventricular mass index, global longitudinal strain, global circumferential strain, mitral annular plane systolic excursion, mitral E/e' ratio, maximum and minimum left atrial (LA) volume index, LA emptying fraction, and left ventricular longitudinal synchrony were evaluated. These measures were related to the incidence of two composite outcomes: cardiovascular disease (CVD) or death and atrial fibrillation (AF) or congestive heart failure (CHF). RESULTS: On follow-up (mean, 8.3 years), there were 241 CVD events or deaths and 139 AF or CHF events. In multivariate-adjusted Cox models, higher LA emptying fraction was associated with a lower risk (hazard ratios per SD, 0.80 and 0.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) while higher minimum LA volume index (hazard ratios per SD, 1.32 and 1.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) and maximum LA volume index (hazard ratios per SD, 1.26 and 1.54 for CVD or death and AF or CHF, respectively; P ≤ .002 for both) were associated with a higher risk for both composite outcomes. CONCLUSIONS: In this community-based sample, LA volumes and function were the best echocardiographic predictors of clinical outcomes. Therefore, these values should be considered for inclusion in standard echocardiographic assessments for the purpose of risk stratification.

Myeloid-related protein 8/14 and high-sensitivity cardiac troponin I to differentiate type 2 myocardial infarction.

Myocardial infarction (MI) not only defines acute MI with obstructed coronary arteries (T1MI) but also myocardial necrosis caused by myocardial oxygen supply/demand mismatch as type 2 MI (T2MI); only T1MI patients benefit from an early invasive management. Myeloid-related protein(MRP)-8/14 is a biomarker described in various inflammatory diseases and in MI patients. Here we evaluate the potential of MRP-8/14 and high-sensitivity troponin I (hs-cTnI) to differentiate T2MI from T1MI. Patients with final diagnosis NSTEMI (n = 254; 33.1% female) enrolled in a prospective biomarker registry between 08/2011 and 10/2016 were analysed. Median baseline MRP-8/14 levels were higher in T2MI (n = 55; 3.37(1.88-6.48)µg/mL) than in T1MI (n = 199; 2.4 [1.4-3.79]µg/mL) (p = .013) patients, in contrast to hs-cTnI (T2MI:52[11.65-321.4]ng/L vs. T1MI:436.5 [61.25-1973.8]ng/L; p < .001). To detect the strength of this association odds ratios(OR) were calculated with MRP-8/14 yielding 2.13(1.16-3.92; p = .015) to predict T2MI and 0.47(0.26-0.87; p = .015) for T1MI. As expected, hs-cTnI yielded an OR of to predict T2MI 0.34(0.17-0.65; p = .001) and 2.98(1.53-5.81; p = .001) for T1MI. Both markers show comparable and independent results if adjust to hs-cTnI/MRP-8/14, TIMI risk score and CRP. T2MI is associated with higher MRP-8/14 and lower hs-cTnI concentrations than T1MI. Our data suggest that MRP-8/14 as a marker of inflammation might provide usable discriminatory information complementing hs-cTnI in a diagnostic procedure evaluating the type of MI directly upon hospital admission.

Bone marrow and plasma FGF-23 in heart failure patients: novel insights into the heart-bone axis.

AIMS: Fibroblast growth factor 23 (FGF-23) is known to be elevated in patients with congestive heart failure (CHF). As FGF-23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF-23 in CHF remains unclear. It is also unclear if FGF-23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF-23 levels measured in bone marrow plasma (FGF-23-BM) and in peripheral blood (FGF-23-P) in CHF patients to gain further insights into the heart-bone axis of FGF-23 expression. We also investigated possible associations between FGF-23-BM as well as FGF-23-P and outcome in CHF patients. METHODS AND RESULTS: We determined FGF-23-P and FGF-23-BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF-23-BM and FGF-23-P with all-cause mortality in CHF patients, 32 events, median follow-up 1673 days, interquartile range [923, 1828]. FGF-23-P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF-23-BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF-23-BM levels were significantly higher than FGF-23-P levels in both CHF patients and in healthy controls (P < 0.001). FGF-23-P and FGF-23-BM correlated significantly with LVEF (r = -0.37 and r = -0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = -0.43 and r = -0.41, respectively) (P for all <0.001) and were independently associated with all-cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18-6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19-6.57], P = 0.018, respectively. CONCLUSIONS: In CHF patients, FGF-23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all-cause mortality. The failing heart seems to interact via FGF-23 within a heart-bone axis.

A Single Visualization Technique for Displaying Multiple Metabolite-Phenotype Associations.

To assist with management and interpretation of human metabolomics data, which are rapidly increasing in quantity and complexity, we need better visualization tools. Using a dataset of several hundred metabolite measures profiled in a cohort of ~1500 individuals sampled from a population-based community study, we performed association analyses with eight demographic and clinical traits and outcomes. We compared frequently used existing graphical approaches with a novel 'rain plot' approach to display the results of these analyses. The 'rain plot' combines features of a raindrop plot and a conventional heatmap to convey results of multiple association analyses. A rain plot can simultaneously indicate effect size, directionality, and statistical significance of associations between metabolites and several traits. This approach enables visual comparison features of all metabolites examined with a given trait. The rain plot extends prior approaches and offers complementary information for data interpretation. Additional work is needed in data visualizations for metabolomics to assist investigators in the process of understanding and convey large-scale analysis results effectively, feasibly, and practically.

Association of Circulating Adipokines With Echocardiographic Measures of Cardiac Structure and Function in a Community-Based Cohort.

BACKGROUND: Adipokines mediate cardiometabolic risk associated with obesity but their role in the pathogenesis of obesity-associated heart failure remains uncertain. We investigated the associations between circulating adipokine concentrations and echocardiographic measures in a community-based sample. METHODS AND RESULTS: We evaluated 3514 Framingham Heart Study participants (mean age 40 years, 53.8% women) who underwent routine echocardiography and had select circulating adipokines measured, ie, leptin, soluble leptin receptor, fatty acid-binding protein 4, retinol-binding protein 4, fetuin-A, and adiponectin. We used multivariable linear regression, adjusting for known correlates (including weight), to relate adipokine concentrations (independent variables) to the following echocardiographic measures (dependent variables): left ventricular mass index, left atrial diameter in end systole, fractional shortening, and E/e'. In multivariable-adjusted analysis, left ventricular mass index was inversely related to circulating leptin and fatty acid-binding protein 4 concentrations but positively related to retinol-binding protein 4 and leptin receptor levels (P≤0.002 for all). Left atrial end-systolic dimension was inversely related to leptin but positively related to retinol-binding protein 4 concentrations (P≤0.0001). E/e' was inversely related to leptin receptor levels (P=0.0002). We observed effect modification by body weight for select associations (leptin receptor and fatty acid-binding protein 4 with left ventricular mass index, and leptin with left atrial diameter in end systole; P<0.05 for interactions). Fractional shortening was not associated with any of the adipokines. No echocardiographic trait was associated with fetuin-A or adiponectin concentrations. CONCLUSIONS: In our cross-sectional study of a large, young to middle-aged, relatively healthy community-based sample, key indices of subclinical cardiac remodeling were associated with higher or lower circulating concentrations of prohypertrophic and antihypertrophic adipokines in a context-specific manner. These observations may offer insights into the pathogenesis of the cardiomyopathy of obesity.

Cardiac Troponins for the Diagnosis of Acute Myocardial Infarction in Chronic Kidney Disease.

Background Patients with chronic kidney disease ( CKD ) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction ( AMI ) without ST -segment elevation ( NSTE ). In patients with CKD , troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE - AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE - AMI . Methods and Results Two cohorts, 1494 patients from a prospective cohort study with high-sensitivity troponin I (hs- cTnI ) measurements and 7059 cases from a clinical registry with high-sensitivity troponin T (hs- cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE - AMI than non- CKD patients. The specificities of hs- cTnI and hs- cTnT to detect NSTE - AMI were reduced with CKD (0.82 versus 0.91 for hs- cTnI and 0.26 versus 0.73 for hs- cTnT ) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs- cTnI ) and 55% (hs- cTnT ) of CKD patients. Conclusions The diagnostic performance of high-sensitivity cardiac troponins in patients with CKD with suspected NSTE - AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.

Adjusted Troponin I for Improved Evaluation of Patients with Chest Pain.

The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = -0.142/-0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.

Urinary neutrophil gelatinase-associated lipocalin and cystatin C compared to the estimated glomerular filtration rate to predict risk in patients with suspected acute myocardial infarction.

INTRODUCTION: Impaired renal function, reflected by estimated glomerular filtration rate (eGFR) or cystatin C, is a strong risk predictor in the presence of acute myocardial infarction (AMI). Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is an early marker of acute kidney injury. uNGAL might also be a good predictor of outcome in patients with cardiovascular disease. Aim of the present study was to evaluate the prognostic value of uNGAL compared to eGFR and cystatin C in patients with suspected AMI. METHODS: 1818 patients were enrolled with suspected AMI. Follow-up information on the combined endpoint of death or non-fatal myocardial infarction was obtained 6months after enrolment and was available in 1804 patients. 63 events (3.5%) were registered. RESULTS: While cystatin C and eGFR were strong risk predictors for the primary endpoint even adjusted for several variables, uNGAL was not independently associated with outcome: When applied continuously uNGAL was associated with outcome but did not remain a statistically significant predictor after several adjustments (i.e. eGFR). By adding cystatin C or uNGAL to GRACE risk score variables, only cystatin C could improve the predictive value while uNGAL showed no improvement. CONCLUSION: We could show that cystatin C is an independent risk predictor in patients with suspected AMI and cystatin C can add improvement to the commonly used GRACE risk score. In contrast uNGAL is not independently associated with outcome and seems not to add further prognostic information to GRACE risk score.