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Vascular reactivity is reflected by blood biomarkers and noninvasive vascular function measurement. The relation of biomarkers to flow-mediated dilation and peripheral arterial tonometry in the general population is little understood. In 5000 individuals (mean age, 56±11 years; age range, 35-74 years; 49% women) of the population-based Gutenberg Health Study we simultaneously assessed 6 biomarkers of cardiovascular function (midregional proadrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro B-type natriuretic peptide, copeptin, C-terminal proendothelin 1, and neopterin) in relation to flow-mediated dilation and peripheral arterial tonometry. Strongest partial correlations (adjusted for age and sex) were observed for baseline pulse amplitude with MR-proADM (r=0.13) and MR-proANP (r=-0.13); hyperemic response variables showed the highest correlation for MR-proADM and peripheral arterial tonometry ratio (r=-0.14). In multivariable linear regression models, strongest associations with baseline vascular function were observed for MR-proANP with baseline pulse amplitude (β per SD increase [99.17%], -0.080 [-0.115 to -0.044]; P<0.0001 after Bonferroni correction for multiple testing) and MR-proADM (-0.044 [-0.070 to -0.017]; P<0.0001), as well as MR-proANP (-0.033 [-0.057 to -0.009]; P=0.0017) and N-terminal pro B-type natriuretic peptide (-0.027 [-0.051 to -0.003]; P=0.015) with brachial artery diameter. For hyperemic response variables, highest associations were seen for peripheral arterial tonometry ratio with MR-proADM (-0.022 [-0.043 to -0.004]; P=0.043), MR-proANP (0.016 [-0.0034 to 0.035]; P=0.18), and C-terminal proendothelin 1 (-0.025 [-0.043 to -0.008]; P=0.00094]. In our large, population-based study, we identified MR-proADM and MR-proANP as circulating biomarkers of vascular function most strongly related to noninvasive measures of conduit artery and peripheral arterial performance. Whether determination of blood biomarkers helps to better understand vascular pathology and may provide prognostic information needs to be investigated in future studies. [ABSTRACT FROM AUTHOR]

Background: Patients with severe tricuspid regurgitation present late and are often ineligible for surgery or transcatheter repair systems. Transfemoral venous implantation of a bicaval valved stent has been proposed as therapeutic option in selected patients. The aim of this study was to summarize the early procedural and clinical outcomes of the novel TRICENTO system for the treatment of patients with symptomatic severe tricuspid regurgitation., Methods: All consecutive patients treated with the custom-made TRICENTO implant at the participating centers were included in this retrospective multicentre registry., Results: A total of 21 high-risk patients (mean age 76±7 years; 67% female) with severe or higher grade tricuspid regurgitation were analyzed. The majority of the patients were in New York Heart Association class III/IV (95%), had peripheral edema (95%), and previous hospitalization for right heart failure (67%). Technical success was 100%, and there was no case of in-hospital mortality. During follow-up (median 61 days), symptomatic improvement was observed (65% in New York Heart Association class I/II; P <0.001). Computed tomography revealed asymptomatic fractures of the TRICENTO prosthesis in 3 patients. Cardiac magnetic resonance imaging obtained in 7 patients showed a significant decrease (252±65 mm 3 at baseline versus 216±58 mm 3 at follow-up, P =0.006) of right ventricular end-diastolic volume. The overall-survival rate was 76% at 1 year., Conclusions: The present data indicate the feasibility of transfemoral bicaval valved stent implantation for the treatment of severe tricuspid regurgitation. Functional improvement and signs of right ventricular reverse remodeling were observed. Stent fractures did not impair valve function, but require refinement of prosthesis design and careful assessment of eligibility criteria.

Background: Scarce data exist on patients with right ventricular dysfunction (RVD) or pulmonary hypertension (PH) undergoing transcatheter tricuspid valve intervention. This study aimed to determine the early and midterm outcomes and the factors associated with mortality in this group of patients., Methods: This subanalysis of the multicenter TriValve (Transcatheter Tricuspid Valve Therapies) registry included 300 patients with severe tricuspid regurgitation with RVD (n=244), PH (n=127), or both (n=71) undergoing transcatheter tricuspid valve intervention. RVD was defined as a tricuspid annular plane systolic excursion <17 mm, and PH as an estimated pulmonary artery systolic pressure ≥50 mm Hg., Results: Mean age of the patients was 77±9 years (54% women). Procedural success was 80.7%, and 9 patients (3%) died during the hospitalization. At a median follow-up of 6 (interquartile range, 2-12) months, 54 patients (18%) died, and the independent associated factors were higher gamma-glutamyl transferase values at baseline (hazard ratio, 1.02 for each increase of 10 u/L [95% CI, 1.002-1.04]), poorer renal function defined as an estimated glomerular filtration rate <45 mL/min (hazard ratio, 2.3 [95% CI, 1.22-4.33]), and the lack of procedural success (hazard ratio, 2.11 [95% CI, 1.17-3.81]). The grade of RVD and the amount of PH at baseline were not found to be predictors of mortality. Most patients alive at follow-up improved their functional class (New York Heart Association I-II in 66% versus 7% at baseline, P <0.001)., Conclusions: In patients with severe tricuspid regurgitation and RVD/PH, transcatheter tricuspid valve intervention was associated with high procedural success and a relatively low in-hospital mortality, along with significant improvements in functional status. However, about 1 out of 5 patients died after a median follow-up of 6 months, with hepatic congestion, renal dysfunction, and the lack of procedural success determining an increased risk. These results may improve the clinical evaluation of transcatheter tricuspid valve intervention candidates and would suggest a closer follow-up in those at increased risk. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03416166.

Background: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD)., Methods and Results: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3))., Conclusions: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

Background: Several methods of noninvasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing., Methods and Results: In 5000 individuals (mean age, 55.5 ± 10.9 years; age range, 35 to 74 years; women, 49.2%) of the population-based Gutenberg Heart Study, we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo (reflection index) and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5-minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman r = 0.17; age- and sex-adjusted partial correlation, 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values but only accounted for 3.2% (reflection index), 15.4% (FMD), and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body mass index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations., Conclusions: Noninvasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies.

Background: Echocardiography, the dominant imaging modality for quantification of left ventricular metrics, has undergone continuing development in the past few decades. However, given the lack of population-based data, current guidelines are still based on restricted and small data sets analyzed with methods including expert opinion. This work presents empirically derived reference values from a large-scale, epidemiologic study conducted with state-of-the-art imaging technology and methods., Methods and Results: The distribution of echocardiographic measurements of the left ventricle was analyzed in a population-based sample of 5000 mid-Europeans from the Gutenberg Heart Study in Germany. The randomly selected, noninstitutionalized sample provides data on apparently healthy individuals, as well as on those with prevalent disease. Standardized echocardiograms were recorded in a comprehensive data set at a single site with centralized training and certification of sonographers. Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms were created by quantile regression. Detailed information is given on the association between left ventricular geometry and age., Conclusions: The rapidly evolving echocardiographic technology with persistent improvements in image quality and new measurement conventions require the evaluation of new reference limits for left ventricular metrics. The present investigation formulates reference limits and nomograms from state-of-the-art technology and methods based on a large population-based data set. The distribution of echocardiographic measures of left ventricular geometry presents, in part, nonlinear associations with age, which should be the subject of future investigations.

Background: Growth-differentiation factor-15 (GDF-15) is a stress-responsive transforming growth factor-beta-related cytokine that has emerged as a prognostic biomarker in acute coronary syndrome trial populations. Its predictive role in stable coronary heart disease (CHD) has never been assessed., Methods and Results: The circulating levels of GDF-15 were measured by immunoradiometric assay in patients with stable angina pectoris (n=1352) or acute coronary syndrome (n=877) who were followed up for a median of 3.6 years. Stable angina pectoris patients presenting with normal (<1200 ng/L), moderately elevated (1200 to 1800 ng/L), or markedly elevated (>1800 ng/L) GDF-15 levels had 3.6-year CHD mortality rates of 1.4%, 2.7%, and 15.0%, respectively (P<0.001). By backward stepwise Cox-regression analysis, which adjusted for age and gender, clinical variables, the number of diseased vessels, renal function, the levels of C-reactive protein, cardiac troponin I, and N-terminal pro-B-type natriuretic peptide, GDF-15 remained an independent predictor of CHD mortality (P<0.001). Addition of GDF-15 improved the prognostic accuracy of a clinical risk prediction model concerning CHD mortality (c-statistic, 0.84 versus 0.74; P=0.005). Analysis of the acute coronary syndrome part of the study population confirmed GDF-15 as an independent predictor of CHD mortality (P<0.001). The circulating levels of GDF-15 did not predict the future risk of nonfatal myocardial infarction in patients with stable angina pectoris or acute coronary syndrome., Conclusions: This study identifies GDF-15 as a strong and independent predictor of CHD mortality across the broad spectrum of patients with stable and unstable CHD.

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6+/-1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 micromol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.