Andrej Teren

Myocardial Infarction-Associated Circular RNA Predicting Left Ventricular Dysfunction.

Identification of patients at risk of developing left ventricular (LV) remodeling and dysfunction after acute myocardial infarction (MI) would represent a major step forward toward personalized medicine. However, predicting outcome after MI is a challenging task, due to the serious limitations of

Impact of angiotensin II on skeletal muscle metabolism and function in mice: contribution of IGF-1, Sirtuin-1 and PGC-1α.

Activation of the renin-angiotensin-aldosterone system and increased levels of angiotensin II (Ang-II) occurs in numerous cardiovascular diseases such as chronic heart failure (CHF). Another hallmark in CHF is a reduced exercise tolerance with impaired skeletal muscle function. The aim of this study was to investigate in an animal model the impact of Ang-II on skeletal muscle function and concomitant molecular alterations. Mice were infused with Ang-II for 4 weeks. Subsequently, skeletal muscle function of the soleus muscle was assessed. Expression of selected proteins was quantified by qRT-PCR and Western blot. Infusion of Ang-II resulted in a 33% reduction of contractile force, despite a lack of changes in muscle weight. At the molecular level an increased expression of NAD(P)H oxidase and a reduced expression of Sirt1, PGC-1α and IGF-1 were noticed. No change was evident for the ubiquitin E3-ligases MuRF1 and MafBx and α-sarcomeric actin expression. Cytophotometrical analysis of the soleus muscle revealed a metabolic shift toward a glycolytic profile. This study provides direct evidence of Ang-II-mediated, metabolic deterioration of skeletal muscle function despite preserved muscle mass. One may speculate that the Ang-II-mediated loss of muscle force is due to an activation of NAD(P)H oxidase expression and a subsequent ROS-induced down regulation of IGF-1, PGC-1α and Sirt1.

Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

Validation of a brief step-test protocol for estimation of peak oxygen uptake

Background Physical exercise capacity has been shown to predict cardiovascular disease incidence and is increasingly measured in epidemiological studies. However, direct measurement of peak oxygen uptake is too time consuming in large-scale studies. We therefore investigated whether a brief 3-minute step-test protocol can be used to estimate peak oxygen uptake in these settings. Design and methods A group of 97 subjects performed the YMCA step test and a maximal treadmill test with continuous measurement of oxygen uptake. Correlation and linear regression analyses were used to identify VO2peak predictors obtained from the step test and to develop models for VO2peak estimation. Results The YMCA model, including the 1-minute heart beat count, predicted VO2peak with R = 0.83. A novel simplified model based on the heart rate at 45 s of recovery performed comparable (R = 0.83). However, models based on heart rate measures were only valid in subjects who completed the test according to protocol, but not in subjects who terminated prematurely. For the applicability in subjects with low exercise capacity, a new model including gas exchange analysis enabled prediction of VO2peak (R = 0.89). All models were validated in an independent sample (r = 0.86–0.91). Exercise time of the step test was less than one-hird of standard ergospirometry (treadmill test: 654 ± 151 s, step test: 180 s, p < 0.001). Conclusion In large-scale epidemiological studies with limited time slots for exercise testing and significant proportions of subjects with low exercise capacity a modified version of the YMCA step test may be used to predict VO2peak.

Validity, intra- and inter-observer reliability of automated devices for the assessment of ankle brachial index using photo-plethysmography

BackgroundAnkle-brachial-Index (ABI) measured by manual Dopplersonography is an easily assessable marker of global cardiovascular risk. The aim of this study was to establish novel photo-plethysmography (PPG)-based ABI assessments in an epidemiologic context and to compare its results with those of Doppler.MethodsTwo devices for PPG-based ABI assessments (Vicorder, Vascular Explorer) were tested and compared against Doppler in 56 putatively healthy subjects. We determined acceptance, time requirements, agreement of repeat measurements, agreement with Doppler and intra- and inter-observer concordances for both devices and compared the results. Differences between cuff inflation- and deflation-based methods were also studied for Vascular Explorer.ResultsAcceptance was similar for both devices but Vascular Explorer was more time consuming. Agreement of multiple measurements was moderate for both methods highlighting the importance of measurement replicates. Both automated devices showed significantly higher ABI compared to Doppler which can be traced back to higher brachial pressures (Vicorder) or higher ankle pressures (Vascular Explorer). This effect is more pronounced for Vascular Explorer but can be ameliorated using the deflation method of measurement. Intra-observer concordances were similar. Inter-observer concordance was non-significantly better for Vicorder.ConclusionsBoth devices proved to be feasible in epidemiologic studies, but compared to Doppler, do not constitute an advantage regarding time requirement and accuracy of ABI assessment. Since PPG-based ABI values are inflated compared to Doppler, it will be necessary to adjust Doppler-based cut-offs for risk stratification.

Relationship Between Determinants of Arterial Stiffness Assessed by Diastolic and Suprasystolic Pulse Oscillometry: Comparison of Vicorder and Vascular Explorer.

AbstractPulse wave velocity (PWV) and augmentation index (AI) are independent predictors of cardiovascular health. However, the comparability of multiple oscillometric modalities currently available for their assessment was not studied in detail. In the present study, we aimed to evaluate the relationship between indices of arterial stiffness assessed by diastolic and suprasystolic oscillometry.In total, 56 volunteers from the general population (23 males; median age 70 years [interquartile range: 65–72 years]) were recruited into observational feasibility study to evaluate the carotid-femoral/aortic PWV (cf/aoPWV), brachial-ankle PWV (baPWV), and AI assessed by 2 devices: Vicorder (VI) applying diastolic, right-sided oscillometry for the determination of all 3 indices, and Vascular explorer (VE) implementing single-point, suprasystolic brachial oscillometry (SSBO) pulse wave analysis for the assessment of cfPWV and AI. Within- and between-device correlations of measured parameters were analyzed. Furthermore, agreement of repeated measurements, intra- and inter-observer concordances were determined and compared for both devices.In VI, both baPWV and cfPWV inter-correlated well and showed good level of agreement with bilateral baPWV measured by VE (baPWV[VI]–baPWV[VE]R: overall concordance correlation coefficient [OCCC] = 0.484, mean difference = 1.94 m/s; cfPWV[VI]–baPWV[VE]R: OCCC = 0.493, mean difference = 1.0 m/s). In contrast, SSBO-derived aortic PWA (cf/aoPWA[VE]) displayed only weak correlation with cfPWV(VI) (r = 0.196; P = 0.04) and ipsilateral baPWV (cf/aoPWV[VE]R–baPWV[VE]R: r = 0.166; P = 0.08). cf/aoPWA(VE) correlated strongly with AI(VE) (right-sided: r = 0.725, P < 0.001). AI exhibited marginal between-device agreement (right-sided: OCCC = 0.298, mean difference: 6.12%). All considered parameters showed good-to-excellent repeatability giving OCCC > 0.9 for 2-point-PWV modes and right-sided AI(VE). Intra- and inter-observer concordances were similarly high except for AI yielding a trend toward better reproducibility in VE (interobserver–OCCC[VI] vs [VE] = 0.774 vs 0.844; intraobserver–OCCC[VI] vs [VE] = 0.613 vs 0.769).Both diastolic oscillometry-derived PWV modes, and AI measured either with VI or VE, are comparable and reliable alternatives for the assessment of arterial stiffness. Aortic PWV assessed by SSBO in VE is not related to the corresponding indices determined by traditional diastolic oscillometry.

Incremental value of Veterans Specific Activity Questionnaire and the YMCA-step test for the assessment of cardiorespiratory fitness in population-based studies

Background Cardiorespiratory fitness is a well-established independent predictor of cardiovascular health. However, the relevance of alternative exercise and non-exercise tests for cardiorespiratory fitness assessment in large cohorts has not been studied in detail. We aimed to evaluate the YMCA-step test and the Veterans Specific Activity Questionnaire (VSAQ) for the estimation of cardiorespiratory fitness in the general population. Methods One hundred and five subjects answered the VSAQ, performed the YMCA-step test and a maximal cardiopulmonary exercise test (CPX) and gave BORG ratings for both exercise tests (BORGSTEP, BORGCPX). Correlations of peak oxygen uptake on a treadmill (VO2_PEAK) with VSAQ, BORGSTEP, one-minute, post-exercise heartbeat count, and peak oxygen uptake during the step test (VO2_STEP) were determined. Moreover, the incremental values of the questionnaire and the step test in addition to other fitness-related parameters were evaluated using block-wise hierarchical regression analysis. Results Eighty-six subjects completed the step test according to the protocol. For completers, correlations of VO2_PEAK with the age- and gender-adjusted VSAQ, heartbeat count and VO2_STEP were 0.67, 0.63 and 0.49, respectively. However, using hierarchical regression analysis, age, gender and body mass index already explained 68.8% of the variance of VO2_PEAK, while the additional benefit of VSAQ was rather low (3.4%). The inclusion of BORGSTEP, heartbeat count and VO2_STEP increased R2 by a further 2.2%, 3.3% and 5.6%, respectively, yielding a total R2 of 83.3%. Conclusions Neither VSAQ nor the YMCA-step test contributes sufficiently to the assessment of cardiorespiratory fitness in population-based studies.

Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes

Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes. Methods: We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290). Results: Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P=1.94×10−17). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P=7.01×10−9) and 7 suggestive hits (P<1×10−6). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness. Conclusions: Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00497887.

Cyclin dependent kinase inhibitor 1 C is a female-specific marker of left ventricular function after acute myocardial infarction

BACKGROUND A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner. METHODS CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up. RESULTS In the test cohort, CDKN1C was lower in patients with a reduced EF (<40%) compared to patients with preserved EF (≥50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort. CONCLUSION CDKN1C is a novel female-specific biomarker of LV function after AMI.

Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15–25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 × 10−5), and regulation of inflammatory response (p = 1.86 × 10−3). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.