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Background: 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., Methods: BAV patients and age-matched healthy controls underwent 4D flow CMR. Regional, peak systolic ascending aortic WSS, aortic valve function, aortic stiffness measures and aortic dimensions were assessed. In BAV patients, 4D flow CMR was repeated after three years follow-up and both at baseline and follow-up computed tomography angiography (CTA) was acquired. Aortic growth (volume increase of ≥5%) was measured on CTA. Regional WSS differences within patients' aorta and WSS changes over time were analysed using linear mixed-effect models and were associated with clinical parameters., Results: Thirty BAV patients (aged 34 years [IQR 25-41]) were included in the follow-up analysis. Additionally, another 16 BAV patients and 32 healthy controls (aged 33 years [IQR 28-48]) were included for other regional analyses. Magnitude, axial, and circumferential WSS increased over time (all p<0.001) irrespective of aortic growth. The percentage of regions exposed to a magnitude WSS >95th percentile of healthy controls increased from 21% (baseline 506/2400 regions) to 31% (follow-up 734/2400 regions) (p<0.001). WSS angle, a measure of helicity near the aortic wall, decreased during follow-up. Magnitude WSS changes over time were associated with systolic blood pressure, peak aortic valve velocity, aortic valve regurgitation fraction, aortic stiffness indexes, and normalized flow displacement (all p<0.05)., Conclusions: An increase of regional WSS over time was observed in BAV patients, irrespective of aortic growth. The increasing WSSs comprising a larger area of the aorta warrants further research to investigate the possible predictive value for aortic dissection., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander Hirsch reports financial support was provided by Thorax Foundation. Jolien Roos-Hesselink reports financial support was provided by Dutch Heart Foundation. Alexander Hirsch reports a relationship with GE Healthcare that includes: consulting or advisory, funding grants, and speaking and lecture fees. Alexander Hirsch reports a relationship with Bayer AG that includes: speaking and lecture fees. Alexander Hirsch reports a relationship with Medis Medical Imaging Systems BV that includes: consulting or advisory. Alexander Hirsch reports a relationship with Cardialysis BV that includes: board membership. Alexander Hirsch is associate editor at the Journal of Cardiovascular Magnetic Resonance. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Competing interests The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, dobutamine stress echocardiography (DSE) is recommended to determine AS severity, whereas the degree of aortic valve calcification (AVC) supposedly correlates with AS severity according to current European and American guidelines., Objectives: The purpose of this study was to assess the relationship between AVC and AS severity as determined using echocardiography and DSE in patients with aortic valve area <1 cm 2 and peak aortic valve velocity <4.0 m/s., Methods: All patients underwent DSE to determine AS severity and multislice computed tomography to quantify AVC. Receiver-operating characteristics curve analysis was used to assess the diagnostic value of AVC for AS severity grading as determined using echocardiography and DSE in men and women., Results: A total of 214 patients were included. Median age was 78 years (25th-75th percentile: 71-84 years) and 25% were women. Left ventricular ejection fraction was reduced (<50%) in 197 (92.1%) patients. Severe AS was diagnosed in 106 patients (49.5%). Moderate AS was diagnosed in 108 patients (50.5%; in 77 based on resting transthoracic echocardiography, in 31 confirmed using DSE). AVC score was high (≥2,000 for men or ≥1,200 for women) in 47 (44.3%) patients with severe AS and in 47 (43.5%) patients with moderate AS. AVC sensitivity was 44.3%, specificity was 56.5%, and positive and negative predictive values for severe AS were 50.0% and 50.8%, respectively. Area under the receiver-operating characteristics curve was 0.508 for men and 0.524 for women., Conclusions: Multi-slice computed tomography-derived AVC scores showed poor discrimination between grades of AS severity using DSE and cannot replace DSE in the diagnostic work-up of low-gradient severe AS., Competing Interests: Funding Support and Author Disclosures Dr Van Mieghem has received grant support/research contracts from Abbott Vascular, Boston Scientific, Medtronic, Edwards Lifesciences, Daiichy Sankyo, AstraZeneca, and PulseCath BV; and has received consulting/speaker fees from Abbot Vascular, Boston Scientific Corporation, Medtronic, Daiichy Sankyo, PulseCath BV, JenaValve, and Amgen. Dr Mehran has received grant support/research contracts from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena Pharmaceuticals, AstraZeneca, Atricure Inc, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, Cytsorbents, Daiichy-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen Pharmaceuticals, Magenta, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave Medical, Vivasure, and Zoll; has received consulting/speaker fees from AstraZeneca, E.R. Squibb and Sons LLC, Esperion Science/Innovativa Biopharma, Ionis Pharmaceuticals, IQVIA, J-Calc, McVeigh Global, Novartis, Novo Nordisk, Overcome, Primer Healthcare of New Jersey, Radcliffe, SL Solutions, TARSUS Cardiology, Vectura, and WebMD; and she has equity in Applied Therapeutics, Elixir, and STEL. Dr Mehran’s spouse has equity in ControlRad. Dr Kodali has received grant support/research contracts from Admedus, Dura Biotech, Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve; has received consulting/speaker fees from Admedus, Dura Biotech, TriCares, X-Dot, Tioga, Helix Valve Repair, and Moray Medical; and has equity in Dura Biotech, Microinterventional Devices, Thubrika Aortic Valve Inc, Supira, Admedus, Triflo, and Adona. Dr Hahn has received consulting/speaker fees from Abbott Structural, Medtronic, Edwards Lifesciences, Boston Scientific, Baylis Medical, Navigate, Philips Healthcare, Siemens Healthcare, and 3mensio; and has equity in Navigate. Dr Bax has received grant support/research contracts from Biotronic, Boston Scientific, Medtronic, Bayer AG, and Edwards Lifesciences; and has received consulting/speaker fees from Abbott Vascular and Edwards Lifesciences. Drs Veulemans and Zeus have received consulting fees, travel expenses, or study honoraria from Medtronic, Edwards Lifesciences, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: N. Van Mieghem received grants or contracts from Abbott, Boston Scientific, Biotronic, Edwards Lifesciences, Medtronic, Pulsecath BV, Abiomed, and Daiichi Sankyo; consulting fees from Jenavalve, Daiichi Sankyo, Abbott, Boston Scientific, and Medtronic; and payment or honoraria for lectures, presentations, speakers, manuscripts, and educational events from Abiomed, Amgen, and Jenavalve. J. Daemen received grants or contracts from Astra Zeneca, Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Microport, Pie Medical, and ReCor Medical, and consultancy and speaker fees from Abbott Vascular, Abiomed, ACIST Medical, Boston Scientific, Cardialysis BV, CardiacBooster, Kaminari Medical, ReCor Medical, PulseCath, Pie Medical, Sanofi, Siemens, and Medtronic. A. Hirsch received grants and consultancy fees from GE Healthcare and speaker fees from GE Healthcare and Bayer, and is also a member of the medical advisory board of Medis Medical Imaging Systems. The other authors had no conflicts to declare.

Background: Transcatheter edge-to-edge repair (TEER) has become an established treatment for primary and secondary mitral regurgitation (PMR and SMR). The objective of this study was to compare the accuracy of different risk scores for predicting 1-year mortality and the composite endpoint of 1-year mortality and/or heart failure (HF) hospitalization after TEER., Methods: We analyzed data from 206 patients treated for MR at a tertiary European center between 2011 and 2023 and compared the accuracy of different mitral and surgical risk scores: EuroSCORE II, GRASP, MITRALITY, MitraScore, TAPSE/PASP-MitraScore, and STS for predicting 1-year mortality and the composite of 1-year mortality and/or HF hospitalization in PMR and SMR. A subanalysis of SMR-only patients with the addition of COAPT Risk Score and baseline N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) list was also performed., Results: MITRALITY had the best discriminative ability for 1-year mortality and the composite endpoint of 1-year mortality and/or HF hospitalization, with an area under the curve (AUC) of 0.74 and 0.74, respectively, in a composed group of PMR and SMR. In a SMR-only population, MITRALITY also presented the best AUC for 1-year mortality and the composite endpoint of 1-year mortality and/or HF hospitalization, with values of 0.72 and 0.72, respectively., Conclusion: MITRALITY was the best mitral TEER risk model for both 1-year mortality and the composite endpoint of 1-year mortality and/or HF hospitalization in a population of PMR and SMR patients, as well as in SMR patients only. Surgical risk scores, MitraScore, TAPSE/PASP-MitraScore and NT-proBNP alone showed poor predictive values., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To describe the clinical outcome and quality of life up to 50 years after surgical atrial septal defect (ASD) closure at young age. Primary outcome is defined as MACE (all-cause mortality, cardiac re-interventions, ischemic stroke, endocarditis, heart failure and symptomatic arrhythmia)., Methods: Single-center, longitudinal cohort-study evaluating 135 consecutive patients who underwent ASD-closure before the age of 15 years between 1968 and 1980. Participants were invited for extensive cardiac evaluation and assessment of quality-of-life every 10 years., Results: Eighty patients (86%) of 93 eligible survivors were included in this study (mean age 52 ± 5 years (range 41-63), 40% male). Median follow-up since surgery was 45 years (range 40-51). Cumulative survival after 50 years was 86% and comparable to the normal Dutch population. Cumulative event-free survival after 45 and 50-years was 59% and 46% respectively (re-intervention in 6, symptomatic arrhythmia in 25, and pacemaker implantation in 10 patients). Right ventricular ejection fraction on CMR was diminished in 6%. Exercise capacity was normal in 77%. There was no pulmonary hypertension. NT-proBNP was elevated in 61%. Quality of life was comparable with the general population. No predictors for late events were identified., Conclusion: Long-term survival after surgical ASD-closure in childhood is good and not statistically different at 50 years compared to the normal Dutch population. Re-intervention rate is low, there is no pulmonary hypertension. Right ventricular function was diminished in 6%, exercise capacity was good and stable over time with quality of life comparable to the general population. However, supraventricular tachycardia is common., Competing Interests: Conflict of interest The authors declare to have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Abdominal aortic aneurysm (AAA) patients undergo uniform surveillance programs both leading up to, and following surgery. Circulating biomarkers could play a pivotal role in individualizing surveillance. We applied a multi-omics approach to identify relevant biomarkers and gain pathophysiological insights., Materials and Methods: In this cross-sectional study, 108 AAA patients and 200 post-endovascular aneurysm repair (post-EVAR) patients were separately investigated. We performed partial least squares regression and ingenuity pathway analysis on circulating concentrations of 96 proteins (92 Olink Cardiovascular-III panel, 4 ELISA-assays) and 199 metabolites (measured by LC-TQMS), and their associations with CT-based AAA/sac volume., Results: The median (25th-75th percentile) maximal diameter was 50.0 mm (46.0, 53.0) in the AAA group, and 55.4 mm (45.0, 64.2) in the post-EVAR group. Correcting for clinical characteristics in AAA patients, the aneurysm volume Z-score differed 0.068 (95 %CI: (0.042, 0.093)), 0.066 (0.047, 0.085) and -0.051 (-0.064, -0.038) per Z-score valine, leucine and uPA, respectively. After correcting for clinical characteristics and orthogonalization in the post-EVAR group, the sac volume Z-score differed 0.049 (0.034, 0.063) per Z-score TIMP-4, -0.050 (-0.064, -0.037) per Z-score LDL-receptor, -0.051 (-0.062, -0.040) per Z-score 1-OG/2-OG and -0.056 (-0.066, -0.045) per Z-score 1-LG/2-LG., Conclusions: The branched-chain amino acids and uPA were related to AAA volume. For post-EVAR patients, LDL-receptor, monoacylglycerols and TIMP-4 are potential biomarkers for sac volume. Additionally, distinct markers for sac change were identified., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Complete revascularization in patients with ST-segment elevation myocardial (STEMI) improves clinical outcome. Vessel fractional flow reserve (vFFR) has been validated as a non-invasive physiological technology to evaluate hemodynamic lesion significance without need for a dedicated pressure wire or hyperemic agent. This study aimed to assess discordance between vFFR reclassification and treatment strategy in intermediate non-culprit lesions of STEMI patients and to assess the clinical impact of this discordance., Methods: This was a single-center, retrospective cohort study. From January 2018 to December 2019, consecutive eligible STEMI patients were screened based on the presence of a non-culprit vessel with an intermediate lesion (30-80% angiographic stenosis) feasible for offline vFFR analysis. The primary outcome was the percentage of non-culprit vessels with discordance between vFFR and actual treatment strategy. The secondary outcome was two-year vessel-oriented composite endpoint (VOCE), a composite of vessel-related cardiovascular death, vessel-related myocardial infarction, and target vessel revascularization., Results: A total of 441 patients (598 non-culprit vessels) met the inclusion criteria. Median vFFR was 0.85 (0.73-0.91). Revascularization was performed in 34.4% of vessels. Discordance between vFFR and actual treatment strategy occurred in 126 (21.1%) vessels. Freedom from VOCE was higher for concordant vessels (97.5%) as compared to discordant vessels (90.6%)(p = 0.003), particularly due to higher adverse event rates in discordant vessels with a vFFR ≤0.80 but deferred revascularization., Conclusions: In STEMI patients with multivessel disease, discordance between vFFR reclassification and treatment strategy was observed in 21.1% of non-culprit vessels with an intermediate lesion and was associated with increased vessel-related adverse events., Competing Interests: Declaration of Competing Interest Nicolas Van Mieghem received institutional research grant support from Abbott Vascular, Abiomed, Boston Scientific, Daiichi-Sankyo, Edward Lifesciences, Medtronic, and PulseCath. Joost Daemen received institutional grant/research support from Abbott Vascular, ACIST Medical, Astra Zeneca, Boston Scientific, Medtronic, Pie Medical, and ReCor Medical. The remaining authors report no relationships that could be construed as a conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: 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.The aim of the contemporary study is to validate a semiautomated calcium quantification scoring tool with a conventional manual calcium quantification tool., Methods: Fifty randomly selected patients who underwent multislice computed tomography for preprocedural planning were retrospectively selected to compare the semiautomated aortic valve Agatston calcium score by 3mensio with the manually obtained score using IntelliSpace Portal as standard reference., Results: Patients had a mean age of 76.7 ± 7.4 years and 60% were male. The median Agatston score was 3390 [interquartile range 1877-4509] with 3mensio and 3434 [interquartile range 1839-4620] with IntelliSpace.The mean difference was -0.18 [95% confidence interval (CI) -53.8 to 53.4]. The intraclass correlation coefficient between the Agatston scores using IntelliSpace and 3mensio showed an excellent correlation of 0.995 [95% CI 0.992-0.997], p ≤ 0.001. The interobserver and intraobserver variability was 0.993 ([95% CI 0.961-0.998], p ≤ 0.001) and 0.995([95%CI 0.981-0.999], p = <0.001), respectively., Conclusions: The semiautomated calcium quantification module in 3mensio Structural Heart highly correlated with a conventional manual calcium scoring tool., Competing Interests: Nicolas M. Van Mieghem received research grants and advisory fees from Abbott, Boston Scientific Corporation, Edwards Lifesciences, Medtronic, Teleflex, Daiichi Sankyo; and from Ancora Heart. Joost Daemen received institutional grant/research support from Astra Zeneca, Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Pie Medical, and ReCor medical. The other authors had no conflicts to declare., (© 2022 The Author(s).)

Background: New permanent pacemaker implantation (new-PPI) remains a compelling issue after Transcatheter Aortic Valve Replacement (TAVR). Previous studies reported the relationship between a short MS length and the new-PPI post-TAVR with a self-expanding THV. However, this relationship has not been investigated in different currently available THV. Therefore, the aim of this study was to investigate the association between membranous septum (MS)-length and new-PPI after TAVR with different Transcatheter Heart Valve (THV)-platforms., Methods: We included patients with a successful TAVR-procedure and an analyzable pre-procedural multi-slice computed tomography. MS-length was measured using a standardized methodology. The primary endpoint was the need for new-PPI within 30 days after TAVR., Results: In total, 1811 patients were enrolled (median age 81.9 years [IQR 77.2-85.4], 54% male). PPI was required in 275 patients (15.2%) and included respectively 14.2%, 20.7% and 6.3% for Sapien3, Evolut and ACURATE-THV(p ​< ​0.01). Median MS-length was significantly shorter in patients with a new-PPI (3.7 ​mm [IQR 2.2-5.1] vs. 4.1 ​mm [IQR 2.8-6.0], p ​= ​<0.01). Shorter MS-length was a predictor for PPI in patients receiving a Sapien3 (OR 0.87 [95% CI 0.79-0.96], p ​= ​<0.01) and an Evolut-THV (OR 0.91 [95% CI 0.84-0.98], p ​= ​0.03), but not for an ACURATE-THV (OR 0.99 [95% CI 0.79-1.21], p ​= ​0.91). By multivariable analysis, first-degree atrioventricular-block (OR 2.01 [95% CI 1.35-3.00], p = <0.01), right bundle branch block (OR 8.33 [95% CI 5.21-13.33], p = <0.01), short MS-length (OR 0.89 [95% CI 0.83-0.97], p ​< ​0.01), annulus area (OR 1.003 [95% CI 1.001-1.005], p ​= ​0.04), NCC implantation depth (OR 1.13 [95% CI 1.07-1.19] and use of Evolut-THV(OR 1.54 [95% CI 1.03-2.27], p ​= ​0.04) were associated with new-PPI., Conclusion: MS length was an independent predictor for PPI across different THV platforms, except for the ACURATE-THV. Based on our study observations within the total cohort, we identified 3 risk groups by MS length: MS length ≤3 ​mm defined a high-risk group for PPI (>20%), MS length 3-7 ​mm intermediate risk for PPI (10-20%) and MS length > 7 ​mm defined a low risk for PPI (<10%). Anatomy-tailored-THV-selection may mitigate the need for new-PPI in patients undergoing TAVR., Competing Interests: Declaration of competing interest Thijmen W. Hokken: none. Mohammed Muhemin: none. Taishi Okuno: none. Verena Veulemans has consulting fees from Medtronic and Edwards lifesciences. Bernardo B. Lopes: none. Alessandro Beneduce: none. Romano Vittorio: none. Joris F. Ooms: none. Rik Adrichem: none. Tara Neleman: none. Isabella Kardys: none. Joost Daemen has received institutional grants from Abbott Vascular, ACIST Medical, Astra Zeneca, Boston Scientific, Medtronic, Microport, Pie Medical and ReCor Medical. A. Chieffo has received speaker/consultant fees from Abbott, Abiomed, Biosensor, Cardinal Health, GADA, and Magenta. Matteo Montorfano has honoraria from Medtronic, Boston Scientific and Abbott. Joao Cavalcante: none. Tobias Zeus has received grants from Medtronic and Edwards lifesciences. Thomas Pilgrim reports research grants to the institution from Edwards Lifesciences, Boston Scientifc and Biotronik, personal fees from Biotronik and Boston Scientific, and other from HighLife SAS. Stefan Toggweiler: has consulting fees from Boston Schientific, Medtronic, Biosensors, Shockwave, Teleflex, Medira, Atheart Medical and VeoSource and stock options from Hi-D imaging. Nicolas M. Van Mieghem received research grants and advisory fees from Abbott, Boston Scientific Corporation, Edwards Lifesciences, Medtronic, Teleflex, Daiichi Sankyo; and from Ancora Heart., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to identify heart failure (HF) subphenotypes using 92 repeatedly measured circulating proteins in 250 patients with heart failure with reduced ejection fraction, and to investigate their clinical characteristics and prognosis., Methods: Clinical data and blood samples were collected tri-monthly until the primary endpoint (PEP) or censoring occurred, with a maximum of 11 visits. The Olink Cardiovascular III panel was measured in baseline samples and the last two samples before the PEP (in 66 PEP cases), or the last sample before censoring (in 184 PEP-free patients). The PEP comprised cardiovascular death, heart transplantation, Left Ventricular Assist Device implantation, and hospitalization for HF. Cluster analysis was performed on individual biomarker trajectories to identify subphenotypes. Then biomarker profiles and clinical characteristics were investigated, and survival analysis was conducted., Results: Clustering revealed three clinically diverse subphenotypes. Cluster 3 was older, with a longer duration of, and more advanced HF, and most comorbidities. Cluster 2 showed increasing levels over time of most biomarkers. In cluster 3, there were elevated baseline levels and increasing levels over time of 16 remaining biomarkers. Median follow-up was 2.2 (1.4-2.5) years. Cluster 3 had a significantly poorer prognosis compared to cluster 1 (adjusted event-free survival time ratio 0.25 (95%CI:0.12-0.50), p < 0.001). Repeated measurements clusters showed incremental prognostic value compared to clusters using single measurements, or clinical characteristics only., Conclusions: Clustering based on repeated biomarker measurements revealed three clinically diverse subphenotypes, of which one has a significantly worse prognosis, therefore contributing to improved (individualized) prognostication., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: 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., Methods: In this single-center prospective study, invasive PVL analysis is performed in patients undergoing transcatheter aortic valve replacement or tricuspid or mitral transcatheter edge-to-edge repair. Clinical follow-up is per standard of care at 1 and 12 months. This study aims to include 75 transcatheter aortic valve replacement patients and 41 patients in both transcatheter edge-to-edge repair cohorts., Results: The primary outcome is the periprocedural change in stroke work, potential energy, and pressure-volume area (mmHg mL -1 ). The secondary outcomes comprise changes in a myriad of parameters obtained by PVL measurements, including ventricular volumes and pressures and the end-systolic elastance-effective arterial elastance ratio as a reflection of ventricular-vascular coupling. A secondary endpoint associates these periprocedural changes in cardiac mechanoenergetics with functional status at 1 month and 1 year., Conclusions: This prospective study aims to elucidate the fundamental changes in cardiac and hemodynamic physiology during contemporary transcatheter valvular interventions., Competing Interests: A.J.M.v.d.E. received personal fees from Abiomed and speaker fees from Angiodynamics. M.B.B. received personal fees from PulseCath. J.J.S. reported working and financial relationship with CD Leycom. J.J.B. received research grants and speaker fees from Abbott. J.D. received institutional grant/research support from Astra Zeneca, Abbott, Boston Scientific, ACIST Medical, Medtronic, Pie Medical, ReCor Medical. N.M.V.M. received grant support from Abbott, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, PulseCath BV, Abiomed, Daiichi Sankyo, Materialise, Pie Medical and Siemens. The other authors have no disclosure., (© 2022 The Author(s).)

Objectives: To describe hemodynamic effects of iVAC2L mechanical circulatory support (MCS)., Background: MCS is increasingly used in the context of high-risk percutaneous coronary intervention (PCI). The effect of the pulsatile iVAC2L MCS on left ventricular loading conditions and myocardial oxygen consumption (MVO 2 ) is unknown., Methods: This prospective single-arm two-center study included 29 patients who underwent high-risk PCI with iVAC2L MCS using simultaneous invasive pulmonary pressure monitoring and left ventricular pressure-volume analysis. Hemodynamic recordings were performed during steady state conditions with MCS off and on before and after PCI. Pressure-volume variations were analyzed to denote responders and non-responders., Results: The mean age was 74 (IQR: 70-81) years and the mean SYNTAX score was 31 ± 8.3. Left ventricular unloading with iVAC2L MCS was demonstrated in 22 out of 27 patients with complete PV studies. Patients with moderate or severe mitral regurgitation or presenting with acute coronary syndrome (ACS) had higher filling pressures and volumes and were most responsive to iVAC2L unloading (9/10 patients with moderate or severe MR and 11/11 patients with ACS). Pulsatile MCS activation reduced MAP (-4%), SBP (-9%), ESP (-11%), ESV (-15%) and EDV (-4%) among responders but not among non-responders. Responders experienced significant reductions in afterload (Ea: -19%) with increases in stroke volume (+11%) and cardiac output (+11%)., Conclusions: Pulsatile iVAC2L MCS in patients with advanced coronary artery disease at high to prohibitive operative risk resulted in LV unloading and reduced myocardial oxygen consumption particularly in patients with ACS or significant MR with higher filling pressures at baseline., Clinical Trial Registration: NCT03200990., Competing Interests: Declaration of competing interest Dr Van Mieghem is advisor and received research grant support from PulseCath B.V. He received institutional research grant support from Abbott Vascular, Boston Scientific, Medtronic, Edwards Lifesciences, Daiichi Sankyo. Dr Bastos received personal fees from PulseCath BV. Dr Daemen received institutional grant/research support from Astra Zeneca, Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Pie Medical, and ReCor medical, and consultancy and speaker fees from Abiomed, ACIST medical, Boston Scientific, ReCor Medical, PulseCath, Pie Medical, Siemens Health Care and Medtronic. Dr Schreuder is an employee of CD Leycom. Mr Malkin is an employee of PulseCath BV. The other authors report no conflicts., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Direct Stenting (DS) could be associated with reduced distal embolization and improved reperfusion in patients with ST-segment elevation myocardial infarction (STEMI). However, the impact of DS on long-term outcomes remains unclear, therefore we evaluated the impact of DS on very long-term clinical outcome in STEMI., Methods/materials: Between April 2002 and December 2004, patients presenting with STEMI undergoing percutaneous coronary intervention were investigated. The study population was divided into two groups: DS and conventional stenting (CS) and stratified according to initial TIMI flow. Major adverse cardiac events (MACE) were assessed at 10 years and all-cause mortality at 15 years. Cox proportional hazards models were used. When the proportional hazards assumption was not satisfied, landmark analysis at mid-term (2 years) was performed., Results: A total of 812 consecutive patients were evaluated, 6 patients were excluded due to inadequate angiographic images, 450 (55.8%) underwent DS and 356 (44.2%) CS. At 15 years follow-up, DS was associated with a reduction in all-cause mortality (DS 35.0% vs. CS 45.3%, aHR 0.74, 95% CI 0.58-0.93, p = 0.010). The landmark analysis at 2 years identifies reduced 2-year MACE in DS compared with CS (6.8% vs.14%, aHR 0.67, 95% CI 0.49-0.93, p = 0.015) and beyond 2 years no significant differences were found between the groups (27.4% vs. 29.3%, aHR 1.00, 95% CI 0.74-1.36, p = 0.999). In patients with baseline TIMI 0-1, DS was associated with lower 10-year MACE and 15-year mortality compared with CS (aHR0.71, 95%CI 0.55-0.92, p = 0.010 and aHR0.65, 95%CI 0.50-0.84, p = 0.001, respectively)., Conclusions: DS was associated with reduced 15-year all-cause mortality and reduced mid-term MACE rate in patients with STEMI. Clinical events reduction associated with DS was particularly relevant in patients with initial TIMI flow 0-1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vessel Fractional Flow Reserve (vFFR) as assessed by three-dimensional quantitative coronary angiography has high correlation with pressure wire-based fractional flow reserve in both a pre- and post-PCI setting. The present study aims to assess the prognostic value of post-PCI vFFR on the incidence of target vessel failure (TVF), a composite endpoint of cardiac death, target vessel myocardial infarction and target vessel revascularization (TVR) at 5-year follow up., Methods: Post-PCI vFFR was calculated after routine PCI in a total of 748 patients (832 vessels) with available orthogonal angiographic projections of the stented segment., Results: Median age was 65 (IQR 55-74) years, 18.2% were diabetic, and 29.1% presented with stable angina. Median post-PCI vFFR was 0.91 (IQR 0.86-0.95). Vessels were categorized into tertiles based on post-PCI vFFR: low (vFFR <0.88), middle (vFFR 0.88-0.93), and upper (vFFR ≥0.94). Vessels in the lower and middle tertile were more often LADs and had smaller stent diameters (p<0.001). Vessels in the lower and middle tertile had a higher risk of TVF as compared to vessels in the upper tertile (24.6% and 21.5% vs. 17.1%; adjusted HR 1.84 (95%CI 1.15-2.95), p = 0.011, and 1.58 (95%CI 1.02-2.45), p = 0.040) at 5-years follow-up. Additionally, vessels in the lower tertile had higher rates of TVR as compared to vessels in the higher tertile (12.6% vs. 6.5%, adjusted HR 1.93 (95%CI 1.06-3.53), p = 0.033)., Conclusion: Lower post-PCI vFFR values are associated with a significantly increased risk of TVF and TVR at 5-years follow-up., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: We aimed to compare conduction dynamics and need for permanent pacemaker implantation (PPI) after CoreValve, Evolut R and PRO (transcatheter aortic valve replacement (TAVR))., Methods: Patients were stratified based on conduction at baseline; Cohort A had normal conduction, Cohort B had conduction abnormalities including atrioventricular (AV)-block, fascicular block or complete bundle branch block. Three different dynamic QRS-patterns were defined: stable QRS-duration, transient QRS-prolongation and persistent QRS-prolongation. We performed multivariable regression analysis to estimate the effect of the three separate transcatheter heart valves (THV's) on need for PPI at 30 days., Results: TAVR was performed with CoreValve (N = 113), Evolut R (N = 157) or Evolut PRO (N = 92). Conduction dynamics were similar between the different THVs. Overall, Evolut R and PRO showed a tendency towards less PPI compared to CoreValve (17% vs. 19% vs. 27%, P = 0.08), which was driven by a lower PPI rate in Cohort A (6% vs. 11% vs. 25%, P = 0.002). Need for PPI was restricted to patients with persistent QRS-prolongation in Cohort A (26/106) but did not correlate with conduction dynamics in Cohort B. In multivariable logistic regression analysis the use of Evolut R (OR 0.38, 95% CI 0.19-0.78, P = 0.008) and PRO (OR 0.41, 95% CI 0.19-0.91, P-value = 0.028) were independently associated with less need for PPI., Conclusion: The newer generations Evolut R and PRO were associated with less PPI compared to CoreValve. Acquired persistent conduction abnormalities predicted PPI after TAVR only in patients with normal conduction at baseline. Our findings may help identify eligible patients for early discharge after Evolut R/PRO TAVR., Competing Interests: Declaration of competing interest HK:no conflicts of interest to declare. LVG:no conflicts of interest to declare. MVW:no conflicts of interest to declare. JO:no conflicts of interest to declare. FZ:no conflicts of interest to declare. ZR:no conflicts of interest to declare. NEF:no conflicts of interest to declare. AM:no conflicts of interest to declare. IK:no conflicts of interest to declare. JD:no conflicts of interest to declare. PDJ:is proctor for Boston Scientific. NVMhas received research grants from Medtronic, Boston scientific, Edwards Lifesciences, Abbott, PulseCath. He is advisor to PulseCath, Ancora, Boston Scientific, Medtronic., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background The need for new permanent pacemaker implantation (PPI) after Transcatheter Aortic Valve Implantation (TAVI) remains a critical issue. Membranous Septum (MS) length is associated with PPI after TAVI. The aim of this study was to identify different MS thresholds for the contemporary THV-platforms. Methods This retrospective, case-control study enrolled all patients who underwent a successful TAVI procedure with contemporary THV-platforms in the Erasmus University Medical Center between January 2016 and March 2020. The follow-up period for new PPI was 30 days. MS-length was determined by Computed Tomography. Results The study consisted 653 TAVI patients with median age 80.6 years (IQR 74.7-84.8). New PPI occurred in 120 patients (18.4%). Patients with new PPI had a shorter MS-length (2.9 mm (IQR 2.3-4.3) vs. 4.2 mm (IQR 2.9-5.7), p < 0.001). MS-length < 3 mm identified a high-risk phenotype with 30.3% PPI-rate (OR 6.5 [95%CI 2.9-14.9]), MS-length 3-6 mm an intermediate-risk phenotype with 15.4% PPI-rate (OR 2.7 [95%CI 1.2-6.2]) and MS > 6 mm a low-risk phenotype with a 6.3% PPI-rate (reference). For the Lotus valve, there was no significant difference in PPI-rates between the high-risk (45.8%, OR 3.5 [95%CI 0.8-15.1]) and low-risk group (20%). By multivariate analysis MS-length, Agatston-score, use of Lotus valve, and ECG with first-degree AV block, RBBB or bifascular block were independent predictors for new PPI. Conclusion MS-length was an independent predictor for new PPI post-TAVI. Three phenotypes were found based on MS-length. MS < 3 mm was universally associated with a high risk for new PPI (>30%). MS > 6 mm represented a low-risk phenotype with PPI-rate < 10%. PPI-rate varied per THV type in the intermediate phenotype. PPI-rate with Lotus was high regardless of MS-length., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Remote magnetic navigation (RMN)-guided catheter ablation (CA) is a feasible treatment option for patients presenting with ischemic ventricular tachycardia (VT). Catheter-tissue contact feedback, enhances lesion formation and may consequently improve CA outcomes. Until recently, contact feedback was unavailable for RMN-guided CA. The novel e-Contact Module (ECM) was developed to continuously monitor and ensure catheter-tissue contact during RMN-guided CA., Objective: The present study aims to evaluate the effect of ECM implementation on acute and long-term outcomes in RMN-guided ischemic VT ablation., Method: This retrospective, two-center study included consecutive ischemic VT patients undergoing RMN-guided CA from 2010 to 2017. Baseline clinical data, procedural data, including radiation times, and acute success rates were compared between CA procedures performed with ECM (ECM+) and without ECM (ECM-). One-year VT-free survival was analyzed using Cox-proportional hazards models, adjusting for potential confounders: age, left ventricular function, VT inducibility at baseline and substrate based ablation strategy., Results: The current study included 145 patients (ECM+ N = 25, ECM- N = 120). Significantly lower fluoroscopy times were observed in the ECM+ group (9.5 (IQR 5.3-13.5) versus 12.5 min (IQR 8.0-18.0), P = 0.025). Non-inducibility of the clinical VT at the end of procedure was observed in 92% ECM+ versus 72% ECM- patients (P = 0.19). ECM guidance was associated with significantly lower VT-recurrence rates during 1-year follow-up (16% ECM+ versus 40% ECM-; multivariable HR 0.29, 95%-CI 0.10-0.69, P = 0.021, reference group: ECM-)., Conclusion: Contact feedback by the ECM further decreases fluoroscopy exposure and improves VT-free survival in RMN-guided ischemic VT ablation., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Although the descending aortic diameter is larger in smokers, data about thoracic aortic growth is missing. Our aim is to present the distribution of thoracic aortic growth in smokers and to compare it with literature of the general population., Methods: Current and ex-smokers aged 50-70 years from the longitudinal Danish Lung Cancer Screening Trial, were included. Mean and 95th percentile of annual aortic growth of the ascending aortic (AA) and descending aortic (DA) diameters were calculated with the first and last non-contrast computed tomography scans during follow-up. Determinants of change in aortic diameter over time were investigated with linear mixed models., Results: A total of 1987 participants (56% male, mean age 57.4 ± 4.8 years) were included. During a median follow-up of 48 months, mean AA and DA growth rates were comparable between males (AA 0.12 ± 0.31 mm/year and DA 0.10 ± 0.30 mm/year) and females (AA 0.11 ± 0.29 mm/year and DA 0.13 ± 0.27 mm/year). The 95th percentile ranged from 0.42 to 0.47 mm/year, depending on sex and location. Aortic growth was comparable between current and ex-smokers and aortic growth was not associated with pack-years. Our findings are consistent with aortic growth rates of 0.08 to 0.17 mm/years in the general population. Larger aortic growth was associated with lower age, increased height, absence of medication for hypertension or hypercholesterolemia and lower Agatston scores., Conclusions: This longitudinal study of smokers in the age range of 50-70 years shows that ascending and descending aortic growth is approximately 0.1 mm/year and is consistent with growth in the general population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFR Cr ] and cystatin C [CysC]., Methods: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFR Cr  ≥ 30 ml/min/1.73 m 2 . Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient)., Results: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2-3. During hospitalization for index ACS (median [IQR] duration: 5 (3-7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03-2.74])., Conclusion: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Our aim was to explore potential use of temporal profiles of seven emerging cardio-renal and two pulmonary candidate biomarkers for predicting future adverse clinical outcome in stable patients with chronic heart failure (CHF)., Methods: In 263 CHF patients, we determined the risk of a composite endpoint of HF-hospitalization, cardiac death, LVAD-placement and heart transplantation in relation to repeatedly assessed (567 samples in total) blood biomarker levels, and slopes of their temporal trajectories (i.e., rate of biomarker change per year). In each patient, we estimated biomarker trajectories using repeatedly measured osteopontin (OPN), osteoprotegerin (OPG), epidermal growth factor receptor (EGFR), heparin-binding protein (HBP), trefoil factor-3 (TFF3), kallikrein-6 (KLK-6), matrix extracellular phosphoglycoprotein (MEPE), pulmonary surfactant-associated protein-D (PSP-D), and secretoglobulin family 3A-member-2 (SCGB3A2)., Results: During 2.2 years of follow-up, OPN, OPG, and HBP levels predicted the composite endpoint (univariable hazard ratio [95% confidence interval] per 1SD increase: 2.31 [1.76-3.15], 2.23 [1.69-3.00], and 1.36[1.09-1.70]). Independently of the biomarkers' levels, the slopes of OPG, TFF-3, PSP-D trajectories were also strong clinical predictors (per 0.1SD increase: 1.24 [1.14-1.38], 1.31 [1.17-1.49], and 1.32 [1.21-1.47]). All associations persisted after multivariable adjustment for baseline characteristics, and repeatedly assessed CHF pharmacological treatment and cardiac biomarkers NT-proBNP and troponin T., Conclusions: Repeatedly-measured levels of OPN, OPG, and HBP, and slopes of OPG, TFF-3, and PSP-D strongly predict clinical outcome. These candidate biomarkers may be clinically relevant as they could further define a patient's risk and provide additional pathophysiological insights into CHF., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: No established reference-standard technique is available for ascending aortic diameter measurements. The aim of this study was to determine agreement between modalities and techniques., Methods: In patients with aortic pathology transthoracic echocardiography, computed tomography angiography (CTA) and magnetic resonance angiography (MRA) were performed. Aortic diameters were measured at the sinus of Valsalva (SoV), sinotubular junction (STJ) and tubular ascending aorta (TAA) during mid-systole and end-diastole. In echocardiography both the inner edge-to-inner edge (I-I edge) and leading edge-to‑leading edge (L-L edge) methods were applied, and the length of the aortic annulus to the most cranial visible part of the ascending aorta was measured. In CTA and MRA the I-I method was used., Results: Fifty patients with bicuspid aortic valve (36 ± 13 years, 26% female) and 50 Turner patients (35 ± 13 years) were included. Comparison of all aortic measurements showed a mean difference of 5.4 ± 2.7 mm for the SoV, 5.1 ± 2.0 mm for the STJ and 4.8 ± 2.1 mm for the TAA. The maximum difference was 18 mm. The best agreement was found between echocardiography L-L edge and CTA during mid-systole. CTA and MRA showed good agreement. A mean difference of 1.5 ± 1.3 mm and 1.8 ± 1.5 mm was demonstrated at the level of the STJ and TAA comparing mid-systolic with end-diastolic diameters. The visible length of the aorta increased on average 5.3 ± 5.1 mmW during mid-systole., Conclusions: MRA and CTA showed best agreement with L-L edge method by echocardiography. In individual patients large differences in ascending aortic diameter were demonstrated, warranting measurement standardization. The use of CTA or MRA is advised at least once., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.)

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., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have suggested circulating microRNAs (miRs) are associated with heart failure, but these studies were small, and limited to single miR measurements. We examined 7 miRs which were previously linked to heart failure, and tested whether their temporal expression level predicts prognosis in a prospective cohort of chronic heart failure (CHF) patients., Methods and Results: In 2011-2013, 263 CHF patients were included. At inclusion and subsequently every 3months, we measured 7miRs. The primary endpoint (PE) comprised heart failure hospitalization, cardiovascular mortality, cardiac transplantation and LVAD implantation. Associations between temporal miR patterns and the PE were investigated by joint modelling, which combines mixed models with Cox regression. Mean age was 67±13years, 72% were men and 27% NYHA classes III-IV. We obtained 873 blood samples (median 3 [IQR 2-5] per patient). The PE was reached in 41 patients (16%) during a median follow-up of 0.9 [0.6-1.4] years. The temporal pattern of miR-22-3p was independently associated with the PE (HR [95% CI] per doubling of level: 0.64 [0.47-0.77]). The instantaneous change in level (slope of the temporal miR pattern) of miR-22-3p was also independently associated with the PE (HR [95% CI] per doubling of slope: 0.33 [0.20-0.51]). These associations remained statistically significant after adjustment for temporal patterns of NT-proBNP, Troponin T and CRP., Conclusions: The temporal pattern of circulating miR-22-3p contains important prognostic and independent information in CHF patients. This concept warrants further investigation in larger series with extended follow-up., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: We investigated whether plasma cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) are associated with intravascular ultrasound (IVUS)-derived characteristics of coronary atherosclerosis and 1-year adverse coronary events in patients with normal and mildly-to-moderately impaired kidney function., Methods: Between 2008 and 2011, virtual histology (VH)-IVUS of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography. Creatinine, CysC and NGAL were measured in pre-procedural blood samples. Presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, lesions with plaque burden (PB)≥70% and lesions with minimal luminal area (MLA)≤4 mm 2 was assessed. Major adverse coronary events (MACE) comprised the composite of all-cause mortality, acute coronary syndrome, or unplanned coronary revascularization. Analyses were stratified using eGFR Cr of 90 ml/min/1.73 m 2 as the cut-off., Results: In patients with normal kidney function, those with higher CysC levels had fewer lesions with PB ≥ 70% and fewer VH-TCFA lesions (adjusted odds ratios (ORs) and 95% confidence intervals (CIs): 0.46 [0.30-0.69] and 0.59 [0.44-0.83], respectively, per standard deviation (SD) ln[ng/mL] CysC). Those with higher NGAL levels also had fewer lesions with PB ≥ 70% (adjusted OR [95% CI]:0.49 [0.29-0.82]) In patients with impaired kidneys, no differences in high-risk lesions were observed for CysC or NGAL. However, those with higher CysC had higher risk of MACE (hazard ratio (HR):1.4, 95% CI [1.03-1.92]). This was not the case in patients with normal kidney function. NGAL did not influence risk of MACE., Conclusions: Mild-to-moderate kidney dysfunction modifies the relationship between CysC and high-risk coronary lesions. This has not been established before, and offers an explanation for the difference in findings between experimental and epidemiologic studies., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Conflicting results exist regarding the association between a common Haptoglobin (Hp) polymorphism and risk of coronary artery disease. We investigated the association of three functionally different anti-oxidant and anti-inflammatory Hp phenotypes (Hp1-1, Hp2-1, Hp2-2) with invasively measured degree and composition of coronary atherosclerosis as determined by intravascular ultrasound (-virtual histology) (IVUS(-VH)) as well as near-infrared spectroscopy (NIRS)., Methods: Non-culprit coronary artery segments of 581 patients with acute coronary syndrome (ACS) or stable angina pectoris were imaged with IVUS(-VH). In 203 patients, the segments were also imaged with NIRS. Pre-procedural blood samples were drawn for Hp phenotyping. Degree (segment plaque volume, segment plaque burden (PB); presence of lesions with PB≥70%) and composition (segment fractions of fibrous, fibro-fatty, dense calcium, and necrotic core tissue; presence of IVUS-VH derived thin-cap fibroatheroma lesions) of coronary atherosclerosis were measured., Results: No differences were present between the three Hp phenotypes with regard to degree and composition of coronary atherosclerosis in the full cohort. However, ACS patients with a Hp2-1 or Hp2-2 phenotype had a higher segment PB percentage (β[95% CI]: 3.88[0.31-7.44], p=0.033), increased prevalence of lesions with PB≥70% (OR[95% CI]: 3.61[1.06-12.30], p=0.040), and a tendency towards a higher segment plaque volume (β[95% CI]: 1.29[-0.04-2.62], p=0.056) in multivariable analyses., Conclusions: Although in the full cohort no associations could be demonstrated between Hp phenotypes and plaque characteristics, a significant association was present between phenotypes resulting from a genotype containing a Hp2 allele (Hp2-1 or Hp2-2) and a higher degree of atherosclerosis in patients with ACS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Experimental studies have suggested that proprotein convertase substilisin/kexin type 9 (PCSK9) might directly promote inflammatory processes contributing to atherosclerosis by mechanisms independent of low-density lipoprotein (LDL) cholesterol levels. This study aims to investigate the association between serum PCSK9 levels and the fraction and amount of necrotic core tissue in coronary atherosclerotic plaque, as assessed by intravascular ultrasound virtual histology (IVUS-VH) imaging., Methods: Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable angina. PCSK9 concentrations were measured in serum samples that were drawn prior to coronary angiography. None of the patients received PCSK9 inhibitors., Results: After adjustment for established cardiac risk factors, statin use and serum LDL cholesterol, serum PCSK9 levels were linearly associated with the fraction of plaque consisting of necrotic core tissue (β = 1.24% increase per 100 μg/L increase in PCKS9, 95%CI 0.55-1.94, p = 0.001) and with the absolute volume of necrotic core tissue (β = 0.09, 95%CI 0.01-0.18, p = 0.033), but were not significantly associated with plaque burden (p = 0.11), plaque volume (p = 0.22) or the presence of IVUS-VH-derived thin-cap fibroatheroma lesions (p = 1.0)., Conclusion: Serum PCSK9 levels were linearly associated with the fraction and amount of necrotic core tissue in coronary atherosclerosis, independently of serum LDL cholesterol levels and statin use. Therefore, PCSK9 may be an interesting therapeutic target for the treatment of atherosclerotic disease beyond LDL cholesterol regulation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: To assess the relationship between the extent and phenotype of coronary atherosclerosis, as assessed by in-vivo grayscale and radiofrequency intravascular ultrasound (IVUS), and circulating Troponin levels in patients with established stable coronary artery disease (CAD)., Methods: In this single-center, cross-sectional analysis, high-sensitivity Troponin T (hsTnT) was measured and IVUS was performed in a predefined non-stenotic segment of a non-culprit coronary artery in 231 patients with stable CAD undergoing elective angiography., Results: HsTnT was detectable (>3 pg/mL) in 212 patients (92%) and a concentration above 14 pg/mL was observed in 19.5%. Normalised segmental plaque volumes were positively associated with hsTnT levels (25.0 mm(3) increase in segmental plaque volume per SD increase in ln-transformed hsTnT, 95% CI: 6.0-44.0, p = 0.010). Higher hsTnT levels were measured in patients with a virtual histology derived thin-cap fibroatheroma (VH-TCFA, adj. odds ratio for presence of VH-TCFA = 1.52 per SD increase in ln-transformed hsTnT, 95% CI: 1.10-2.11, p = 0.011). Patients with a VH-TCFA had a 2-fold increased prevalence of hsTnT concentration ≥14 pg/mL (adj. OR 2.35, 95% CI: 1.12-4.91, p = 0.024). In addition, a 3-fold increased prevalence of hsTnT concentration ≥14 pg/mL was observed in patients with a VH-TCFA with a lesional plaque volume higher than the median (adj. OR 3.36, 95% CI: 1.44-7.84, p = 0.005)., Conclusions: Segmental plaque volume and presence of VH-TCFA lesions are associated with higher circulating hsTnT concentrations in stable CAD patients. Subclinical plaque rupture or erosion and distal embolisation may be hypothesized as a potential pathophysiological mechanism with respect to Troponin elevation and its relation with adverse outcome in this patient population., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Previous lipidomics analyses have demonstrated that several lipid molecules in plasma are associated with fatal outcome in patients with coronary artery disease (CAD). This study aims to investigate the associations of previously identified high risk lipid molecules in plasma with coronary plaque characteristics derived from intravascular ultrasound virtual histology (IVUS-VH) imaging, with coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS), and with one year cardiovascular outcome in patients with CAD., Methods: Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable CAD. NIRS imaging was additionally performed in 191 patients. Plasma concentrations of molecular lipids were measured with mass spectrometry., Results: Several cholesteryl ester, ceramide and lactosylceramide species and ceramide ratios were associated with vulnerable plaque characteristics on IVUS-VH and NIRS imaging and with 1-year major adverse cardiac events (MACE, defined as all-cause mortality, ACS and unplanned coronary revascularization). In particular, ceramide d18:1/16:0 was consistently associated with higher necrotic core fraction on IVUS-VH (p = 0.001), higher LCBI (p = 0.024) on NIRS and higher MACE rate (adjusted HR 1.79 per standard deviation increase in log-transformed lipid concentration, 95%CI 1.24-2.59, p = 0.002)., Conclusion: Several molecular lipid species, and particularly ceramide(d18:1/16:0), are associated with the fraction of necrotic core tissue and lipid core burden in coronary atherosclerosis, and are predictive for 1-year clinical outcome after coronary angiography. These molecular lipids may improve risk stratification in CAD and may also be interesting therapeutic targets for the treatment of atherosclerotic disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Adult congenital heart disease (ACHD) patients are at risk of late complications including arrhythmias, heart failure and sudden death. High-sensitive troponin-T (hs-TnT) is the standard for diagnosing acute coronary syndrome, but is also associated with cardiac function and prognosis in other cardiac diseases. We aimed to describe hs-TnT level in ACHD patients, and determine its relationship with cardiac function and other biomarkers., Methods: Consecutive ACHD patients, visiting the outpatient clinic, underwent echocardiography, exercise testing and venipuncture on the same day., Results: In total 587 patients were included (median age 33 [IQR 25-41] years, 58% male, 90% NYHA class I). hs-TnT was above the detection limit of 5 ng/L in 241 patients (41%), of whom 47 (8%) had hs-TnT levels above the 99th percentile of normal of 14 ng/L. hs-TnT levels were highest in patients with a systemic RV or pulmonary hypertension. Patients with normal or non-detectable hs-TnT were younger (32 [IQR 24-40] years) than patient with elevated hs-TnT (42 [IQR 36-60] years, p<0.001). The prevalence of hs-TnT ≥14 ng/L was higher in patients with NYHA ≥II (36%, p<0.001), systemic systolic dysfunction (38%, p<0.001), non-sinus rhythm (43%, p<0.001) and elevated pulmonary pressures (39%, p<0.001). hs-TnT was correlated with NT-proBNP (r=0.400, p<0.001)., Conclusions: hs-TnT above the 99th percentile of normal is observed in a non-trivial portion of stable ACHD patients, especially in those with a systemic RV or elevated pulmonary pressures. Since this biomarker of myocardial damage is related to NT-proBNP and ventricular function, its potential predictive value in ACHD patients seems promising and further investigation of underlying mechanisms is warranted., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: We examined whether the acute phase proteins (APPs): Alpha-1-Antitrypsin, Alpha-2-Macroglobulin, Complement C3, ferritin, haptoglobin, and Plasminogen Activator Inhibitor 1 (PAI-1) are associated with cardiovascular outcome, as well as with the extent and composition of coronary atherosclerosis as determined by intravascular ultrasound (IVUS) virtual histology (VH)., Methods: In 2008-2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients from the ATHEROREMO-IVUS study undergoing coronary angiography for acute coronary syndrome (ACS) (n=318) or stable angina pectoris (SAP) (n=263). Coronary atherosclerotic plaque volume, composition (fibrous, fibro-fatty, dense calcium and necrotic core) and vulnerability (VH-derived thin-cap fibroatheroma (TCFA) lesions) were assessed. Major adverse cardiac events (MACE; all-cause mortality, ACS or unplanned coronary revascularization) were assessed during 1-year follow-up. We applied linear, logistic and Cox regression., Results: Mean age was 61.5 ± 11.4 years and 75.4% were men. Higher ferritin was associated with higher coronary plaque volume (beta [95% CI]: 0.19 [0.07-0.31] percent atheroma volume), for the highest vs the lowest tertile of ferritin; p for linear association=0.013. Higher PAI-1 was associated with higher rates of all-cause mortality or ACS (hazard ratio [95% CI]: 2.98 [1.10-8.06]), for the highest vs the lowest tertile of PAI-1. No clear-cut associations could be demonstrated between APPs and composition of atherosclerosis or plaque vulnerability., Conclusions: Higher circulating ferritin was associated with higher coronary plaque volume, and higher PAI-1 was associated with higher incidence of all-cause mortality or ACS. None of the APPs displayed consistent associations with composition of atherosclerosis or plaque vulnerability., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Previous studies have suggested positive associations between periodontal infection and cardiovascular disease. We aimed to investigate the associations of circulating antibodies against periodontal pathogens with 1-year cardiovascular outcome, as well as the extent of coronary atherosclerosis, plaque vulnerability and lesion remodeling on intravascular ultrasound (IVUS) imaging., Methods: Between 2008 and 2011, radiofrequency IVUS imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography. Immunoglobulin G (IgG) and A (IgA) against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Prevotella intermedia were measured in plasma., Results: None of the antibody levels were associated with coronary plaque burden, radiofreqeuncy-IVUS-derived thin-cap fibroatheroma lesion morphology or 1-year incidence of major adverse cardiac events (MACE), which included all-cause mortality, acute coronary syndrome and unplanned coronary revascularization. IgA against A. actinomycetemcomitans, T. forsythia and P. intermedia were inversely associated with extent of positive lesion remodeling (OR for highest versus lowest tertile 0.55, 95%CI 0.35-0.88, p = 0.012; 0.53, 95%CI 0.32-0.87, p = 0.012; and 0.64, 95%CI 0.40-1.02, p = 0.061, respectively). In diabetic patients specifically, IgG against P. gingivalis tended to be associated with coronary plaque burden (p = 0.080), while IgA against P. gingivalis tended to be associated with incident MACE (p = 0.060)., Conclusion: Plasma IgG and IgA against major periodontal pathogens were not associated with the extent of coronary atherosclerosis (with the exception of a trend in diabetics) nor with coronary plaque vulnerability. IgA against periodontal pathogens were inversely associated with extent of coronary remodeling. Altogether, these results do not add evidence for a substantial role of systemic exposure to periodontal pathogens in coronary artery disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: We investigated whether concentrations of TNF-α, TNF-β, TNF-receptor 2, interferon-γ, IL-6, IL-8, IL-10 and IL-18 are associated with extent and composition of coronary atherosclerosis determined by grayscale and virtual histology (VH)- intravascular ultrasound (IVUS)., Methods: Between 2008 and 2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients (stable angina pectoris (SAP), n = 261; acute coronary syndrome (ACS), n = 309) undergoing coronary angiography from the ATHEROREMO-IVUS study. Plaque burden, presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, and presence of VH-TCFA lesions with plaque burden ≥70% were assessed. Blood samples for cytokine measurement were drawn from the arterial sheath prior to the angiography procedure. We applied linear and logistic regression., Results: TNF-α levels were positively associated with plaque burden (beta (β) [95%CI]: 4.45 [0.99-7.91], for highest vs lowest TNF-α tertile) and presence of VH-TCFA lesions (odds ratio (OR) [95%CI] 2.30 (1.17-4.52), highest vs lowest TNF-α tertile) in SAP patients. Overall, an inverse association was found between IL-10 concentration and plaque burden (β [95%CI]: -1.52 [-2.49 to -0.55], per Ln (pg/mL) IL-10) as well as IL-10 and VH-TCFA lesions with plaque burden ≥70% (OR: 0.31 [0.12-0.80],highest vs lowest IL-10 tertile). These effects did not reach statistical significance in the separate SAP and ACS groups., Conclusion: Higher circulating TNF-α was associated with higher plaque burden and VH-TCFA lesions in SAP patients. Lower circulating IL-10 was associated with higher plaque burden and large VH-TCFA lesions. These in-vivo findings suggest a role for these cytokines in extent and vulnerability of atherosclerosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Little evidence is available on the optimal sequence of intra-aortic balloon pump (IABP) support initiation and primary percutaneous coronary intervention (PCI) in patients who present with cardiogenic shock from ST-elevation myocardial infarction (STEMI). The aim of this study was to evaluate the order of IABP insertion and primary PCI and its association with infarct size and mortality., Methods: A series of 173 consecutive patients admitted with cardiogenic shock from STEMI and treated with primary PCI and IABP between 2000 and 2009 were included. The order of IABP insertion and primary PCI was left at the discretion of the interventional cardiologist., Results: All baseline characteristics were similar in patients who first received IABP (n=87) and patients who received IABP directly after PCI (n=86). In these two groups, cumulative 30-day mortality was 44% and 37% respectively (p=0.39). Median peak serum creatine kinase (CK) concentrations were 5692 U/l and 4034 U/l respectively (p=0.048). In multivariable analysis, IABP insertion before PCI was independently associated with higher CK levels (p=0.046). In patients who survived 30 days, IABP insertion before PCI was not associated with late mortality evaluated at five years of follow-up (HR1.5, 95% CI 0.7-3.3; p=0.34)., Conclusions: Early IABP insertion before primary PCI might be associated with higher peak CK levels, indicating a larger infarct size. A possible explanation may be the increased reperfusion delay. Our study suggests that early reperfusion could have priority over routine early IABP insertion in STEMI patients with cardiogenic shock. Randomized studies are needed to determine the optimal timing of IABP insertion relative to primary PCI., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Even when heart failure has not yet become clinically manifest, preclinical ventricular dysfunction may be present, and therapeutic interventions introduced at this time may reduce morbidity and mortality. However, data on the predictive value of echocardiographic characteristics in the general population remain relatively scarce., Methods: The Rotterdam Study is a population-based cohort study in men and women aged >or=55 years. Participants with prevalent heart failure, myocardial infarction and atrial fibrillation and flutter at the time of echocardiography were excluded. Structural, systolic and diastolic parameters were assessed using two-dimensional, M-mode and Doppler echocardiography. Echocardiograms were available in 4425 participants., Results: During a mean follow-up of 3.0 years, 226 participants died. Increased left ventricular mass was an independent risk factor for all-cause mortality, particularly in men (hazard ratio per standard deviation of natural log transformed left ventricular mass, 1.20 (95% CI, 1.01-1.43)). Fractional shortening and left ventricular systolic function did not show a clear association with mortality. E/A ratio <0.75 was an independent risk factor in men (age-adjusted hazard ratio 1.82 (95% CI 1.23-2.69)). This was further reflected by diastolic function: impaired relaxation was a risk factor in men, but not in women., Conclusions: Structural and diastolic echocardiographic parameters are associated with all-cause mortality in an asymptomatic population. However, the evidence is still inadequate to support the usefulness of echocardiography for screening to identify asymptomatic individuals with preclinical ventricular dysfunction.

Aims: Although prospective studies have unequivocally shown that C-reactive protein (CRP) is an independent predictor of future cardiovascular events, studies on the association between CRP and atherosclerosis have provided inconsistent results. We investigated the association of CRP with extent and progression of atherosclerosis in multiple vessel beds in a large, population-based cohort study., Methods: In the Rotterdam Study, standardized measurements of coronary and extra-coronary atherosclerosis were performed in 1962 persons and 6582 persons, respectively. Progression of extra-coronary atherosclerosis during a mean follow-up period of 6.4 years was assessed in 3757 persons., Results: Independent and graded associations were found of CRP with the number of carotid plaques and carotid plaque progression ((OR 1.72; 95% CI 1.14-2.59) for severe progression in participants with CRP>3mg/dl versus participants with CRP<1mg/dl). Similarly, CRP was independently and graded related to ankle-brachial-index (ABI) and worsening ABI over the years ((OR 1.99; 95% CI 1.37-2.88) for severe progression in participants with CRP>3mg/dl versus participants with CRP<1mg/dl). Although CRP was independently related to the highest level of carotid intima-media thickness (IMT), the association with change in IMT was not significant. Furthermore, there was an independent, graded relation between CRP and aortic calcification, but no independent association was observed with progression of aortic calcification, nor with the amount of coronary calcification., Conclusion: In this population-based study, independent and graded associations were present of CRP with extent and progression of carotid plaques and ABI, while associations with carotid IMT and aortic and coronary calcification were less pronounced.

Objective: Inflammation plays a role in the pathogenesis of dementia and Alzheimer's disease (AD). Studies examining serum levels of C-reactive protein in relation to dementia yielded conflicting results. Since serum levels of C-reactive protein are partly determined by genetic factors, we examined the association between genetic variation in the C-reactive protein gene with dementia and AD., Methods: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly. Polymorphisms in the C-reactive protein gene (1184C>T, 2042C>T and 2911C>G) tagging the common haplotypes were genotyped and haplotypes were constructed. During follow-up (mean 9.2 years) 607 dementia cases were identified. We estimated the association between polymorphisms and haplotypes with dementia and AD with Cox' proportional hazard models., Results: The T allele of the C-reactive protein 2042C>T polymorphism, related to lower serum levels of C-reactive protein, was associated with a lower risk of dementia and AD. This association was strongest in APOE epsilon4 allele carriers., Conclusion: These findings suggest that C-reactive protein plays a role in development of dementia.

Objectives: Although several studies have recently suggested that lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent predictor of coronary events, only one study has examined the association between Lp-PLA2 and coronary calcification, using young adults. We investigated the association between Lp-PLA2 activity and coronary calcification assessed by electron-beam computed tomography (EBT) in a population of older participants., Methods and Results: The Rotterdam Coronary Calcification Study is a population-based study in men and women aged >/=55 years. Coronary calcification assessed by EBT was quantified in a calcium score according to Agatston's method. Lp-PLA2 activity measured in samples collected 7 years before scanning (n=520) was associated with coronary calcification in men after adjustment for age. The odds ratio per standard deviation of Lp-PLA2 activity of having a total calcium score >1000 was 1.6 (95% confidence interval: 1.1-2.4), as compared to a total calcium score