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AbstractIntroductionPatients who have experienced an acute coronary syndrome (ACS) are at risk of a recurrent event, but their level of risk varies. Because of their close temporal relationship with vascular injury, longitudinal measurements of circulating endothelial cells (CECs) carry potential to improve individual risk assessment.MethodsWe conducted an explorative nested case-control study within our multicenter, prospective, observational biomarker study (BIOMArCS) of 844 ACS patients. Following an index ACS, high-frequency blood sampling was performed during 1-year follow-up. CECs were identified using flow cytometric analyses in 15 cases with recurrent event, and 30 matched controls.ResultsCases and controls had a median (25th-75thpercentile) age of 64.1 (58.1-75.1) years and 80% were men. During the months preceding the endpoint, the mean (95%CI) CEC concentration in cases was persistently higher than in controls (12.8 [8.2-20.0] versus10.0 [7.0-14.4] cells/ml), although this difference was non-significant (P = 0.339). In controls, the mean cell concentration was significantly (P = 0.030) lower in post 30-day samples compared to samples collected within one day after index ACS: 10.1 (7.5-13.6) versus17.0 (10.8-26.6) cells/ml. Similar results were observed for CEC subsets co-expressing CD133 and CD309 (VEGFR-2) or CD106 (VCAM-1).ConclusionDespite their close relation to vascular damage, no increase in cell concentrations were found prior to the occurrence of a secondary adverse cardiac event.

ObjectiveWomen with Turner syndrome (TS) are at increased risk of aortic dissection, which is a life-threatening event associated with aortic dilation. Knowledge on the development of aortic dilation over time remains limited. This study aims to describe the prevalence of aortic dilation, to find associated factors and to study aortic growth in women with TS.MethodsIn this prospective multicentre cohort study, consecutive adult women with genetically proven TS included between 2014 and 2016 underwent ECG-triggered multiphase CT angiography at baseline and after 3 years. Aortic diameters were measured at seven levels of the thoracic aorta using double oblique reconstruction and indexed for body surface area. Ascending aortic dilation was defined as an aortic size index >20 mm/m2. Aorta-related and cardiovascular events were collected. Statistical analysis included linear and logistic regression and linear mixed effects models.ResultsThe cohort consisted of 89 women with a median age of 34 years (IQR: 24–44). Ascending aortic dilation was found in 38.2% at baseline. At baseline, age (OR: 1.08 (95% CI 1.03 to 1.13), p<0.001), presence of bicuspid aortic valve (BAV) (OR: 7.09 (95% CI 2.22 to 25.9), p=0.002) and systolic blood pressure (OR: 1.06 (95% CI 1.02 to 1.11), p=0.004) were independently associated with ascending aortic dilation. During a median follow-up of 3.0 (2.4–3.6) years (n=77), significant aortic growth was found only at the sinotubular junction (0.20±1.92 mm, p=0.021). No aortic dissection occurred, one patient underwent aortic surgery and one woman died.ConclusionsIn women with TS, ascending aortic dilation is common and associated with age, BAV and systolic blood pressure. Aortic diameters were stable during a 3-year follow-up, apart from a significant yet not clinically relevant increase at the sinotubular junction, which may suggest a more benign course of progression than previously reported.

AbstractPurposeHigher soluble ST2 (sST2) levels at admission are associated with adverse outcome in acute coronary syndrome (ACS) patients. We studied the dynamics of sST2 over time in post-ACS patients prior to a recurrent ACS or cardiac death.MethodsWe used the BIOMArCS case cohort, consisting of 187 patients who underwent serial blood sampling during one-year follow-up post-ACS. sST2 was batch-wise quantified after completion of follow-up in a median of 8 (IQR: 5–11) samples per patient. Joint modelling was used to investigate the association between longitudinally measured sST2 and the endpoint, adjusted for gender, GRACE risk score and history of cardiovascular diseases.ResultsMedian age was 64 years and 79% were men. The 36 endpoint patients had systematically higher sST2 levels than those that remained endpoint free (mean value 29.6 ng/ml versus 33.7 ng/ml, p-value 0.052). The adjusted hazard ratio for the endpoint per standard deviation increase of sST2 was 1.64 (95% confidence interval: 1.09–2.34; p = 0.019) at any time point. We could not identify a steady or sudden increase of sST2 in the run-up to the combined endpoint.ConclusionAsymptomatic post-ACS patients with persistently higher sST2 levels are at higher risk of recurrent ACS or cardiac death during one-year follow-up.

Background: High mortality and rehospitalization rates demonstrate that improving risk assessment in heart failure patients remains challenging. Individual temporal evolution of kidney biomarkers is associated with poor clinical outcome in these patients and hence may carry the potential to move towards a personalized screening approach. Methods: In 263 chronic heart failure patients included in the prospective Bio-SHiFT cohort study, glomerular and tubular biomarker measurements were serially obtained according to a pre-scheduled, fixed trimonthly scheme. The primary endpoint (PE) comprised cardiac death, cardiac transplantation, left ventricular assist device implantation or heart failure hospitalization. Personalized scheduling of glomerular and tubular biomarker measurements was compared to fixed scheduling in individual patients by means of a simulation study, based on clinical characteristics of the Bio-SHiFT study. For this purpose, repeated biomarker measurements and the PE were jointly modeled. For personalized scheduling, using this fitted joint model, we determined the optimal time point of the next measurement based on the patient’s individual risk profile as estimated by the joint model and the maximum information gain on the patient’s prognosis. We compared the schedule’s capability of enabling timely intervention before the occurrence of the PE and number of measurements needed. Results: As compared to a pre-defined trimonthly scheduling approach, personalized scheduling of glomerular and tubular biomarker measurements showed similar performance with regard to prognostication, but required a median of 0.4–2.7 fewer measurements per year. Conclusion: Personalized scheduling is expected to reduce the number of patient visits and healthcare costs. Thus, it may contribute to efficient monitoring of chronic heart failure patients and could provide novel opportunities for timely adaptation of treatment. Graphic abstract:

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment.

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AbstractPurpose:The aim of this study was to study temporal changes in metabolite profiles in patients with post-acute coronary syndrome (ACS), in particular prior to the development of recurrent ACS (reACS).Methods:BIOMArCS (BIOMarker study to identify the Acute risk of a Coronary Syndrome) is a prospective study including patients admitted for ACS, who underwent high-frequency blood sampling during 1-year follow-up. Within BIOMArCS, we performed a nested case-cohort analysis of 158 patients (28 cases of reACS). We determined 151 metabolites by nuclear magnetic resonance in seven (median) blood samples per patient. Temporal evolution of the metabolites and their relation with reACS was assessed by joint modelling. Results are reported as adjusted (for clinical factors) hazard ratios (aHRs).Results:Median age was 64 (25th–75th percentiles; 56–72) years and 78% were men. After multiple testing correction (p < 0.001), high concentrations of extremely large very low density lipoprotein (VLDL) particles (aHR 1.60/SD increase; 95%CI 1.25–2.08), very large VLDL particles (aHR 1.60/SD increase; 95%CI 1.25–2.08) and large VLDL particles (aHR 1.56/SD increase; 95%CI 1.22–2.05) were significantly associated with reACS. Moreover, these longitudinal particle concentrations showed a steady increase over time prior to reACS. Among the other metabolites, no significant associations were observed.Conclusion:Post-ACS patients with persistent high concentrations of extremely large, very large and large VLDL particles have increased risk of reACS within 1 year.

ABSTRACTBackground:Vascular complications (VCs) after transcatheter aortic valve implantation (TAVI) are associated with impaired outcome. We performed a meta-analysis to determine in-hospital/30-day major VCs rate after transfemoral-TAVI adjudicated by an independent clinical-event-committee, and to compare the major VCs rate with regard to consecutive generations of balloon-expandable and self-expanding platforms, device profile, experience and patient risk-profile.Methods:A systematic, computerized search with predefined criteria was performed in PubMed, Embase and Cochrane on March 27, 2018. The overall pooled proportion of VC was calculated using a random-effects model. Subgroups were examined based on sheath size, STS-score and start-date of inclusion (early (< January 2012); late-phase (≥ January 2012) studies).Results:A total of 24 studies with 14308 patients were included. The pooled major VCs rate was 7.71% and was lower in low-profile vs. high-profile device studies (5.51% vs. 8.46%, p= 0.0015). Major VCs rate decreased significantly with transition to newer generation balloon-expandable valves ((Sapien vs. Sapien XT (15.18% vs. 8.48%, p< 0.00001); Sapien XT vs. Sapien 3 (8.48% vs. 4.48%, p= 0.005)) and there was a tendency towards fewer major VCs in EvolutR vs. CoreValve (5.98% vs. 7.97%, p= 0.094). Major VC rate was lower in late-phase vs. early-phase studies (5.82% vs. 7.84%, p= 0.048) and a tendency towards a lower rate was seen in intermediate vs. high-risk studies (7.09% vs. 9.62%, p= 0.059).Conclusion:The pooled rate of independently adjudicated major VCs after transfemoral-TAVI was 7.71%. Experience and device profile are associated with fewer major VCs.

Aortic wall shear stress (WSS) is a known predictor of ascending aortic growth in patients with a bicuspid aortic valve (BAV). The aim of this study was to study regional WSS and changes over time in BAV patients.

ABSTRACTBackground:Myocardial injury (MI) is common with transcatheter aortic valve implantation (TAVI) and may predict poor outcome. We aim: 1) to evaluate the difference in change of high-sensitivity-Troponin-T (hsTnT) within 24h after transfemoral-TAVI between mechanically-expanded (MEV), self-expanding (SEV) and balloon-expandable-valves (BEV); 2) to determine predictors for MI post-TAVI; and 3) to assess whether MI is associated with 30-day mortality.Methods:This multicenter retrospective observational study included 1208 consecutively treated transfemoral-TAVI patients from three European centers. All patients treated with a MEV, SEV or BEV with available hsTnT measurements at baseline and within 24 h post-TAVI were included. Significant MI was defined as an elevation of hsTnT ≥ 15x the upper-reference-limit.Results:Overall, the median hsTnT rise was 741 ng/L and was lower with MEV (MEV 335 vs. SEV 901 vs. BEV 649 ng/L, p< 0.001). MI occurred in 925 patients (77%) and was less frequent with MEV (MEV 67%, SEV 79% and BEV 76%, p= 0.007). Occurrence of MI was similar after implantation of first vs. second- generation SEV (79 vs. 80%, p= 0.72) and BEV (77 vs. 76%, p= 0.90). There was no association between frequency of annulus manipulation and MI. On multivariable analysis (OR (95% CI) non-MEV (1.63 (1.06–2.49)), mean aortic gradient (1.02 (1.01–1.03)), left ventricular ejection fraction (1.03 (1.01–1.04)), and previous myocardial infarction (1.62 (1.04–2.56)) were positively associated with MI. There was no association between MI and 30-day mortality.Conclusion:Transcatheter valve design determines peri-procedural MI and is less frequent with MEV. MI is not associated with 30-day mortality.

We aimed to compare the prognostic value of a single “baseline” echocardiogram with repeated echocardiography in stable chronic heart failure (CHF) patients. We hypothesized that repeated echocardiograms would contain incremental prognostic information.

AbstractPurpose:We assessed the temporal pattern of 29 immune and inflammatory proteins in post-acute coronary syndrome (ACS) patients, prior to the development of recurrent ACS.Methods:High-frequency blood sampling was performed in 844 patients admitted for ACS during one-year follow-up. We conducted a case-control study on the 45 patients who experienced reACS (cases) and two matched event-free patients (controls) per case. Olink Proteomics’ immunoassay was used to obtain serum levels of the 29 proteins, expressed in an arbitrary unit on the log2-scale (Normalized Protein eXpression, NPX). Linear mixed-effects models were applied to examine the temporal pattern of the proteins, and to illustrate differences between cases and controls.Results:Mean age was 66 ± 12 years and 80% were men. Cases and controls had similar baseline clinical characteristics. During the first 30 days, and after multiple testing correction, cases had significantly higher serum levels of CXCL1 (difference of 1.00 NPX, p = 0.002), CD84 (difference of 0.64 NPX, p = 0.002) and TNFRSF10A (difference of 0.41 NPX, p < 0.001) than controls. After 30 days, serum levels of all 29 proteins were similar in cases and controls. In particular, no increase was observed prior to reACS.Conclusions:Among 29 immune and inflammatory proteins, CXCL1, CD84 and TNFRSF10A were associated with early reACS after initial ACS-admission.

Multiple hormonal and metabolic alterations occur in chronic heart failure (CHF), but their proper monitoring during clinically silent progression of CHF remains challenging. Hence, our objective was to explore whether temporal patterns of six emerging cardiometabolic biomarkers predict future adverse clinical events in stable patients with CHF.

We investigated the associations of ten previously identified high risk molecular lipid species and three ceramide ratios with the occurrence of major adverse cardiac events (MACEs) during a median follow-up of 4.7 years in patients with coronary artery disease (CAD). Between 2008 and 2011, 581 patients underwent diagnostic coronary angiography or percutaneous coronary intervention for stable angina pectoris (SAP) or acute coronary syndrome (ACS). Blood was drawn prior to the index procedure and lipid species were determined. The primary endpoint was the occurrence of a MACE, comprising all-cause mortality, nonfatal ACS, or unplanned coronary revascularization. The secondary endpoint comprised all-cause mortality or nonfatal ACS. During a median follow-up of 4.7 [IQR: 4.2–5.6] years, 155 patients (27%) had MACEs. In multivariable analyses, Cer(d18:1/16:0) concentration was associated with MACEs {hazard ratio 2.32; 95% CI [1.09–4.96] per natural logarithm (ln) (pmol/ml) P= 0.030} after adjustment for cardiac risk factors, clinical presentation, statin use at baseline, and admission nonHDL cholesterol level. Furthermore, after multivariable adjustment, concentrations of Cer(d18:1/16:0), Cer(d18:1/20:0), Cer(d18:1/24:1), and their ratios to Cer(d18:1/24:0) were associated with the composite endpoint death or nonfatal ACS. The data together show the circulating ceramide lipids we investigated here are associated with adverse cardiac outcome during long-term follow-up independent of clinical risk factors.

In nephrology, repeated measures are frequently available (glomerular filtration rate or proteinuria) and linked to adverse outcomes. However, several features of these longitudinal data should be considered before making such inferences. These considerations are discussed, and we describe how joint modeling of repeatedly measured and time-to-event data may help to assess disease dynamics and to derive personalized prognosis. Joint modeling combines linear mixed-effects models and Cox regression model to relate patient-specific trajectory to their prognosis. We describe several aspects of the relationship between time-varying markers and the endpoint of interest that are assessed with real examples to illustrate the aforementioned aspects of the longitudinal data provided. Thus, joint models are valuable statistical tools for study purposes but also may help health care providers in making well-informed dynamic medical decisions.

Renal dysfunction is an important component of chronic heart failure (CHF), but its single assessment does not sufficiently reflect clinically silent progression of CHF prior to adverse clinical outcome. Therefore, we aimed to investigate temporal evolutions of glomerular and tubular markers in 263 stable patients with CHF, and to determine if their patient-specific evolutions during this clinically silent period can dynamically predict clinical outcome. We determined the risk of clinical outcome (composite endpoint of Heart Failure hospitalization, cardiac death, Left Ventricular Assist Device placement, and heart transplantation) in relation to marker levels, slopes and areas under their trajectories. In each patient, the trajectories were estimated using repeatedly measured glomerular markers: creatinine/estimated glomerular filtration rate (eGFR), cystatin C (CysC), and tubular markers: urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1, plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL). During 2.2 years of follow-up, we collected on average 8 urine and 9 plasma samples per patient. All glomerular markers predicted the endpoint (univariable hazard ratio [95% confidence interval] per 20% increase: creatinine: 1.18[1.07–1.31], CysC: 2.41[1.81–3.41], and per 20% eGFR decrease: 1.13[1.05–1.23]). Tubular markers, NAG, and KIM-1 also predicted the endpoint (NAG: 1.06[1.01–1.11] and KIM-1: 1.08[1.04–1.11]). Larger slopes were the strongest predictors (creatinine: 1.57[1.39–1.84], CysC: 1.76[1.52–2.09], eGFR: 1.59[1.37–1.90], NAG: 1.26[1.11–1.44], and KIM-1: 1.64[1.38–2.05]). Associations persisted after multivariable adjustment for clinical characteristics. Thus, during clinically silent progression of CHF, glomerular and tubular functions deteriorate, but not simultaneously. Hence, patient-specific evolutions of these renal markers dynamically predict clinical outcome in patients with CHF.

Aortic valve calcification correlates with the severity of aortic valve stenosis and a high calcium score is associated with conduction disturbances and paravalvular leakage after transcatheter aortic valve replacement. The 3mensio Structural Heart is a semiautomated software package to facilitate aortic root analysis by multislice computed tomography.

Introduction:Subphenotyping of HF may lead to pathophysiological insights and treatment opportunities. We aimed to identify novel circulating-protein based subphenotypes (SP) in patients with HFrEF. We used repeated proteomic assessments to account for the dynamic nature of HF.Methods:In 382 patients, we performed trimonthly blood sampling during a median follow-up of 2.1 years. We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, LVAD implantation, and heart transplantation) or censoring and applied an aptamer-based multiplex proteomic approach. We used unsupervised machine learning to derive subphenotypes from 4210 protein trajectories per patient represented by linear mixed effect intercept and slope coefficients.Results:We identified 4 SPs. SP1 was older with higher SBP, EF and history of hypertension. SP2 was older with lower SBP, lower EF, more comorbidities, and worse prognosis (adjHR(95% CI): 4.06 (2.07-7.96)) compared to SP1. SP3 was younger, had lower SBP and EF, more frequently cardiomyopathy (in particular dilated), and a worse prognosis (2.70 (1.33-5.48)). SP4 contained few patients and thus was harder to interpret. It differed from SP3 via higher SBP, higher EF, and seemingly better prognosis. SP allocation was driven by subsets of proteins associated with various biological functions and diseases, e.g. myocardial stress, inflammation, and renal dysfunction. Clinical characteristics of the SPs were aligned with these associations. The prognostic model using SPs based on repeated measurements had a better fit than using SPs based on baseline values (c-index: 0.78 vs 0.72).Conclusions:We found 4 circulating-protein based HFrEF subphenotypes driven by varying protein subsets, with different clinical characteristics and prognosis. Repeated protein measurements improved discriminative ability of the subphenotypes for clinical outcomes.

Aims: Early risk stratification is important in patients with cardiogenic shock from ST-elevation myocardial infarction (STEMI). We aimed to develop a simple risk chart that includes clinical parameters that are readily available at time of hospital admission to assess risk of 30-day mortality.Methods and results: A series of 544 STEMI patients admitted to undergo primary percutaneous coronary intervention and presenting with cardiogenic shock were included between 2000 and 2012. Overall 30-day mortality was 38.4% and did not change over the years (p-trend=0.64). Baseline variables that were available at time of hospital admission were entered into a logistic regression model in a forward stepwise manner. Only age (odds ratio (OR) per year 1.05, 95% confidence interval (CI) 1.04–1.07, p<0.001), initial serum lactate level (OR per mmol/l 1.17, 95% CI 1.11–1.24, p<0.001) and initial creatinine level above the upper limit of normal (OR 2.89, 95% CI 1.90–4.37, p<0.001) remained independent predictors, and were subsequently used to develop a risk chart that stratifies risk of 30-day mortality into categories ranging from 0–20% to 80–100%. The calibration plot showed a close relationship between expected and observed mortality. The risk chart had a higher discriminative accuracy than the GRACE score (c-index 0.75 vs. 0.66, p=0.009). Adding variables that were obtained from coronary angiography and during clinical course did not significantly improve discriminative accuracy of risk chart (c-index 0.77, p=0.48).Conclusion: Mortality of patients with cardiogenic shock from STEMI undergoing primary percutaneous coronary intervention can be well predicted already at time of hospital admission by a risk chart that uses only three variables, namely, age, initial serum lactate and creatinine level.

Transcatheter valvular interventions affect cardiac and hemodynamic physiology by changing ventricular (un-)loading and metabolic demand as reflected by cardiac mechanoenergetics. Real-time quantifications of these changes are scarce. Pressure-volume loop (PVL) monitoring appraises both load-dependent and load-independent compounds of cardiac physiology including myocardial work, ventricular unloading, and ventricular-vascular interactions. The primary objective is to describe changes in physiology induced by transcatheter valvular interventions using periprocedural invasive biventricular PVL monitoring. The study hypothesizes transcatheter valve interventions modify cardiac mechanoenergetics that translate into improved functional status at 1-month and 1-year follow-up.

Studies on the prognostic value of serial biomarker assays for future occurrence of allograft rejection (AR) are scarce. We examined whether repeated measurements of NT-pro-B-type natriuretic peptide (NT-proBNP), troponin T (TropT) and C-reactive protein (CRP) predict AR.

AbstractObjective: To investigate relations of several circulating chemokines with extent and phenotype of coronary atherosclerosis and with 1-year clinical outcome.Methods: Intravascular ultrasound virtual histology (IVUS-VH) imaging of a coronary artery was performed in 581 patients. Monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-1β and regulated upon activation normal T cell expressed and secreted (RANTES) were measured in plasma.Results: Higher MCP-1, MIP-1α and lower RANTES were associated with coronary plaque burden. Higher MCP-1, MIP-1α and lower RANTES were associated with the presence of IVUS-VH-derived thin-cap fibroatheroma lesions. RANTES was associated with major adverse cardiac events.Conclusions: RANTES is a promising biomarker that is inversely associated with coronary plaque burden and vulnerability, as well as with death and acute coronary syndrome.Trial registration:ClinicalTrials.gov identifier: NCT01789411.

Arterial stiffness increases with age and predicts cardiovascular disease. Fibrinogen is an acute-phase protein and some studies showed an association with arterial stiffness. We studied genetic variation in the fibrinogen-α (FGA) and fibrinogen-γ (FGG) genes, by means of single nucleotide polymorphisms (FGA −58 G/A, 1374 G/A, 1526 T/C, 312 Thr/Ala, and FGG 4288 G/A, 6326 G/A, 7792 T/C) and resultant haplotypes in relation to arterial stiffness.

It remains unclear whether C-reactive protein (CRP) is a serum marker for atherothrombotic disease or a causal factor in the pathogenesis of atherosclerosis. We explored the association between CRPgene variations and cerebral small-vessel disease (SVD) in the Rotterdam Scan Study (N1035) and the MEMO Study (N268).