Publications by authors named "Nina W van der Hoeven"

32 Publications

Targeted Temperature Management in Out-of-Hospital Cardiac Arrest With Shockable Rhythm: A Post Hoc Analysis of the Coronary Angiography After Cardiac Arrest Trial.

Crit Care Med 2021 Sep 22. Epub 2021 Sep 22.

Department of Cardiology, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands. Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Department of Cardiology, Amphia Hospital, Breda, The Netherlands. Department of Intensive Care Medicine, Amphia Hospital, Breda, The Netherlands. Department of Cardiology, Rijnstate Hospital, Arnhem, The Netherlands. Department of Intensive Care Medicine, Rijnstate Hospital, Arnhem, The Netherlands. Department of Cardiology, HAGA Hospital, Den Haag, The Netherlands. Department of Intensive Care Medicine, HAGA Hospital, Den Haag, The Netherlands. Department of Cardiology, Maasstad Hospital, Rotterdam, The Netherlands. Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Maasstad Hospital, Rotterdam, The Netherlands. Department of Intensive Care Medicine, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Maastricht University Medical Center, University Maastricht, Maastricht, The Netherlands. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Medisch Spectrum Twente, Enschede, The Netherlands. Department of Cardiology, Medisch Spectrum Twente, Enschede, The Netherlands. Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Cardiology, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands. Department of Intensive Care Medicine, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands. Department of Cardiology, OLVG, Amsterdam, The Netherlands. Department of Intensive Care Medicine, OLVG, Amsterdam, The Netherlands. Department of Cardiology, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands. Department of Intensive Care Medicine, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands. Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands. Department of Cardiology, Scheper Hospital, Emmen, The Netherlands. Department of Cardiology, Haaglanden Medical Center, Den Haag, The Netherlands. Department of Cardiology, Isala Hospital, Zwolle, The Netherlands. Department of Cardiology, Tergooi Hospital, Blaricum, The Netherlands. Department of Cardiology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands. Department of Epidemiology and Data Science, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands.

Objectives: The optimal targeted temperature in patients with shockable rhythm is unclear, and current guidelines recommend targeted temperature management with a correspondingly wide range between 32°C and 36°C. Our aim was to study survival and neurologic outcome associated with targeted temperature management strategy in postarrest patients with initial shockable rhythm.

Design: Observational substudy of the Coronary Angiography after Cardiac Arrest without ST-segment Elevation trial.

Setting: Nineteen hospitals in The Netherlands.

Patients: The Coronary Angiography after Cardiac Arrest trial randomized successfully resuscitated patients with shockable rhythm and absence of ST-segment elevation to a strategy of immediate or delayed coronary angiography. In this substudy, 459 patients treated with mild therapeutic hypothermia (32.0-34.0°C) or targeted normothermia (36.0-37.0°C) were included. Allocation to targeted temperature management strategy was at the discretion of the physician.

Interventions: None.

Measurements And Main Results: After 90 days, 171 patients (63.6%) in the mild therapeutic hypothermia group and 129 (67.9%) in the targeted normothermia group were alive (hazard ratio, 0.86 [95% CI, 0.62-1.18]; log-rank p = 0.35; adjusted odds ratio, 0.89; 95% CI, 0.45-1.72). Patients in the mild therapeutic hypothermia group had longer ICU stay (4 d [3-7 d] vs 3 d [2-5 d]; ratio of geometric means, 1.32; 95% CI, 1.15-1.51), lower blood pressures, higher lactate levels, and increased need for inotropic support. Cerebral Performance Category scores at ICU discharge and 90-day follow-up and patient-reported Mental and Physical Health Scores at 1 year were similar in the two groups.

Conclusions: In the context of out-of-hospital cardiac arrest with shockable rhythm and no ST-elevation, treatment with mild therapeutic hypothermia was not associated with improved 90-day survival compared with targeted normothermia. Neurologic outcomes at 90 days as well as patient-reported Mental and Physical Health Scores at 1 year did not differ between the groups.
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http://dx.doi.org/10.1097/CCM.0000000000005271DOI Listing
September 2021

Cardiac MRI to Visualize Myocardial Damage after ST-Segment Elevation Myocardial Infarction: A Review of Its Histologic Validation.

Radiology 2021 10 24;301(1):4-18. Epub 2021 Aug 24.

From the Department of Cardiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands (C.W.H.B., L.S.F.K., S.E.M., N.v.R., R.N.); Department of Cardiology, Amsterdam University Medical Center, Amsterdam, the Netherlands (N.W.v.d.H., H.E., A.C.v.R.); Department of Medicine, Duke University School of Medicine, Durham, NC (R.J.K.); Department of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands (S.C.A.M.B.); Huntington Medical Research Institutes, Pasadena, Calif (R.A.K.); and Division of Cardiovascular Medicine, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, Calif (R.A.K.).

Cardiac MRI is a noninvasive diagnostic tool using nonionizing radiation that is widely used in patients with ST-segment elevation myocardial infarction (STEMI). Cardiac MRI depicts different prognosticating components of myocardial damage such as edema, intramyocardial hemorrhage (IMH), microvascular obstruction (MVO), and fibrosis. But how do cardiac MRI findings correlate to histologic findings? Shortly after STEMI, T2-weighted imaging and T2* mapping cardiac MRI depict, respectively, edema and IMH. The acute infarct size can be determined with late gadolinium enhancement (LGE) cardiac MRI. T2-weighted MRI should not be used for area-at-risk delineation because T2 values change dynamically over the first few days after STEMI and the severity of T2 abnormalities can be modulated with treatment. Furthermore, LGE cardiac MRI is the most accurate method to visualize MVO, which is characterized by hemorrhage, microvascular injury, and necrosis in histologic samples. In the chronic setting post-STEMI, LGE cardiac MRI is best used to detect replacement fibrosis (ie, final infarct size after injury healing). Finally, native T1 mapping has recently emerged as a contrast material-free method to measure infarct size that, however, remains inferior to LGE cardiac MRI. Especially LGE cardiac MRI-defined infarct size and the presence and extent of MVO may be used to monitor the effect of new therapeutic interventions in the treatment of reperfusion injury and infarct size reduction. © RSNA, 2021
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http://dx.doi.org/10.1148/radiol.2021204265DOI Listing
October 2021

Left ventricular function, strain, and infarct characteristics in patients with transient ST-segment elevation myocardial infarction compared to ST-segment and non-ST-segment elevation myocardial infarctions.

Eur Heart J Cardiovasc Imaging 2021 Jul 1. Epub 2021 Jul 1.

Department of Cardiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Aims: This study aims to explore cardiovascular magnetic resonance (CMR)-derived left ventricular (LV) function, strain, and infarct size characteristics in patients with transient ST-segment elevation myocardial infarction (TSTEMI) compared to patients with ST-segment and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI, respectively).

Methods And Results: In total, 407 patients were enrolled in this multicentre observational prospective cohort study. All patients underwent CMR examination 2-8 days after the index event. CMR cine imaging was performed for functional assessment and late gadolinium enhancement to determine infarct size and identify microvascular obstruction (MVO). TSTEMI patients demonstrated the highest LV ejection fraction and the most preserved global LV strain (longitudinal, circumferential, and radial) across the three groups (overall P ≤ 0.001). The CMR-defined infarction was less frequently observed in TSTEMI than in STEMI patients [77 (65%) vs. 124 (98%), P < 0.001] but was comparable with NSTEMI patients [77 (65%) vs. 66 (70%), P = 0.44]. A remarkably smaller infarct size was seen in TSTEMI compared to STEMI patients [1.4 g (0.0-3.9) vs. 13.5 g (5.3-26.8), P < 0.001], whereas infarct size was not significantly different from that in NSTEMI patients [1.4 g (0.0-3.9) vs. 2.1 g (0.0-8.6), P = 0.06]. Whilst the presence of MVO was less frequent in TSTEMI compared to STEMI patients [5 (4%) vs. 53 (31%), P < 0.001], no significant difference was seen compared to NSTEMI patients [5 (4%) vs. 5 (5%), P = 0.72].

Conclusion: TSTEMI yielded favourable cardiac LV function, strain, and infarct-related scar mass compared to STEMI and NSTEMI. LV function and infarct characteristics of TSTEMI tend to be more similar to NSTEMI than STEMI.
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http://dx.doi.org/10.1093/ehjci/jeab114DOI Listing
July 2021

Transient ST-elevation myocardial infarction versus persistent ST-elevation myocardial infarction. An appraisal of patient characteristics and functional outcome.

Int J Cardiol 2021 08 15;336:22-28. Epub 2021 May 15.

Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV Amsterdam, the Netherlands; Department of Cardiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, the Netherlands. Electronic address:

Background: Up to 24% of patients presenting with ST-elevation myocardial infarction (STEMI) show resolution of ST-elevation and symptoms before revascularization. The mechanisms of spontaneous reperfusion are unclear. Given the more favorable outcome of transient STEMI, it is important to obtain further insights in differential aspects.

Methods: We compared 251 patients who presented with transient STEMI (n = 141) or persistent STEMI (n = 110). Clinical angiographic and laboratory data were collected at admission and in subset of patients additional index hemostatic data and at steady-state follow-up. Cardiac magnetic resonance imaging (CMR) was performed at 2-8 days to assess myocardial injury.

Results: Transient STEMI patients had more cardiovascular risk factors than STEMI patients, including more arterial disease and higher cholesterol values. Transient STEMI patients showed angiographically more often no intracoronary thrombus (41.1% vs. 2.7%, P < 0.001) and less often a high thrombus burden (9.2% vs. 40.0%, P < 0.001). CMR revealed microvascular obstruction less frequently (4.2% vs. 34.6%, P < 0.001) and smaller infarct size [1.4%; interquartile range (IQR), 0.0-3.7% vs. 8.8%; IQR, 3.9-17.1% of the left ventricle, P < 0.001] with a better preserved left ventricular ejection fraction (57.8 ± 6.7% vs. 52.5 ± 7.6%, P < 0.001). At steady state, fibrinolysis was higher in transient STEMI, as demonstrated with a reduced clot lysis time (89 ± 20% vs. 99 ± 25%, P = 0.03).

Conclusions: Transient STEMI is a syndrome with less angiographic thrombus burden and spontaneous infarct artery reperfusion, resulting in less myocardial injury than STEMI. The presence of a more effective fibrinolysis in transient STEMI patients may explain these differences and might provide clues for future treatment of STEMI.
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http://dx.doi.org/10.1016/j.ijcard.2021.05.018DOI Listing
August 2021

The effect of immediate coronary angiography after cardiac arrest without ST-segment elevation on left ventricular function. A sub-study of the COACT randomised trial.

Resuscitation 2021 07 28;164:93-100. Epub 2021 Apr 28.

Department of Intensive care medicine, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands.

Background: The effect of immediate coronary angiography and percutaneous coronary intervention (PCI) in patients who are successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) on left ventricular function is currently unknown.

Methods: This prespecified sub-study of a multicentre trial evaluated 552 patients, successfully resuscitated from out-of-hospital cardiac arrest without signs of STEMI. Patients were randomized to either undergo immediate coronary angiography or delayed coronary angiography, after neurologic recovery. All patients underwent PCI if indicated. The main outcomes of this analysis were left ventricular ejection fraction and end-diastolic and systolic volumes assessed by cardiac magnetic resonance imaging or echocardiography.

Results: Data on left ventricular function was available for 397 patients. The mean (± standard deviation) left ventricular ejection fraction was 45.2% (±12.8) in the immediate angiography group and 48.4% (±13.2) in the delayed angiography group (mean difference: -3.19; 95% confidence interval [CI], -6.75 to 0.37). Median left ventricular end-diastolic volume was 177 ml in the immediate angiography group compared to 169 ml in the delayed angiography group (ratio of geometric means: 1.06; 95% CI, 0.95-1.19). In addition, mean left ventricular end-systolic volume was 90 ml in the immediate angiography group compared to 78 ml in the delayed angiography group (ratio of geometric means: 1.13; 95% CI 0.97-1.32).

Conclusion: In patients successfully resuscitated after out-of-hospital cardiac arrest and without signs of STEMI, immediate coronary angiography was not found to improve left ventricular dimensions or function compared with a delayed angiography strategy.

Clinical Trial Registration: Netherlands Trial Register number, NTR4973.
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http://dx.doi.org/10.1016/j.resuscitation.2021.04.020DOI Listing
July 2021

Data on sex differences in one-year outcomes of out-of-hospital cardiac arrest patients without ST-segment elevation.

Data Brief 2020 Dec 12;33:106521. Epub 2020 Nov 12.

Department of Intensive care medicine, Maastricht University Medical Center, University Maastricht, Maastricht, the Netherlands.

Sex differences in out-of-hospital cardiac arrest (OHCA) patients are increasingly recognized. Although it has been found that post-resuscitated women are less likely to have significant coronary artery disease (CAD) than men, data on follow-up in these patients are limited. Data for this data in brief article was obtained as a part of the randomized controlled Coronary Angiography after Cardiac Arrest without ST-segment elevation (COACT) trial. The data supplements the manuscript "Sex differences in out-of-hospital cardiac arrest patients without ST-segment elevation: A COACT trial substudy" were it was found that women were less likely to have significant CAD including chronic total occlusions, and had worse survival when CAD was present. The dataset presented in this paper describes sex differences on interventions, implantable-cardioverter defibrillator (ICD) shocks and hospitalizations due to heart failure during one-year follow-up in patients successfully resuscitated after OHCA. Data was derived through a telephone interview at one year with the patient or general practitioner. Patients in this randomized dataset reflects a homogenous study population, which can be valuable to further build on research regarding long-term sex differences and to further improve cardiac care.
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http://dx.doi.org/10.1016/j.dib.2020.106521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691722PMC
December 2020

Sex differences in patients with out-of-hospital cardiac arrest without ST-segment elevation: A COACT trial substudy.

Resuscitation 2021 01 12;158:14-22. Epub 2020 Nov 12.

Department of Intensive care medicine, Maastricht University Medical Centre, University Maastricht, Maastricht, the Netherlands.

Background: Whether sex is associated with outcomes of out-of-hospital cardiac arrest (OHCA) is unclear.

Objectives: This study examined sex differences in survival in patients with OHCA without ST-segment elevation myocardial infarction (STEMI).

Methods: Using data from the randomized controlled Coronary Angiography after Cardiac Arrest (COACT) trial, the primary point of interest was sex differences in OHCA-related one-year survival. Secondary points of interest included the benefit of immediate coronary angiography compared to delayed angiography until after neurologic recovery, angiographic and clinical outcomes.

Results: In total, 522 patients (79.1% men) were included. Overall one-year survival was 59.6% in women and 63.4% in men (HR 1.18; 95% CI: 0.76-1.81;p = 0.47). No cardiovascular risk factors were found that modified survival. Women less often had significant coronary artery disease (CAD) (37.0% vs. 71.3%;p < 0.001), but when present, they had a worse prognosis than women without CAD (HR 3.06; 95% CI 1.31-7.19;p = 0.01). This was not the case for men (HR 1.05; 95% CI 0.67-1.65;p = 0.83). In both sexes, immediate coronary angiography did not improve one-year survival compared to delayed angiography (women, odds ratio (OR) 0.87; 95% CI 0.58-1.30;p = 0.49; vs. men, OR 0.97; 95% CI 0.45-2.09;p = 0.93).

Conclusion: In OHCA patients without STEMI, we found no sex differences in overall one-year survival. Women less often had significant CAD, but when CAD was present they had worse survival than women without CAD. This was not the case for men. Both sexes did not benefit from a strategy of immediate coronary angiography as compared to delayed strategy with respect to one-year survival.

Clinical Trial Registration Number: Netherlands trial register (NTR) 4973.
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http://dx.doi.org/10.1016/j.resuscitation.2020.10.026DOI Listing
January 2021

Coronary Angiography After Cardiac Arrest Without ST Segment Elevation: One-Year Outcomes of the COACT Randomized Clinical Trial.

JAMA Cardiol 2020 Dec;5(12):1358-1365

Department of Cardiology, Scheper Hospital, Emmen, the Netherlands.

Importance: Ischemic heart disease is a common cause of cardiac arrest. However, randomized data on long-term clinical outcomes of immediate coronary angiography and percutaneous coronary intervention (PCI) in patients successfully resuscitated from cardiac arrest in the absence of ST segment elevation myocardial infarction (STEMI) are lacking.

Objective: To determine whether immediate coronary angiography improves clinical outcomes at 1 year in patients after cardiac arrest without signs of STEMI, compared with a delayed coronary angiography strategy.

Design, Setting, And Participants: A prespecified analysis of a multicenter, open-label, randomized clinical trial evaluated 552 patients who were enrolled in 19 Dutch centers between January 8, 2015, and July 17, 2018. The study included patients who experienced out-of-hospital cardiac arrest with a shockable rhythm who were successfully resuscitated without signs of STEMI. Follow-up was performed at 1 year. Data were analyzed, using the intention-to-treat principle, between August 29 and October 10, 2019.

Interventions: Immediate coronary angiography and PCI if indicated or coronary angiography and PCI if indicated, delayed until after neurologic recovery.

Main Outcomes And Measures: Survival, myocardial infarction, revascularization, implantable cardiac defibrillator shock, quality of life, hospitalization for heart failure, and the composite of death or myocardial infarction or revascularization after 1 year.

Results: At 1 year, data on 522 of 552 patients (94.6%) were available for analysis. Of these patients, 413 were men (79.1%); mean (SD) age was 65.4 (12.3) years. A total of 162 of 264 patients (61.4%) in the immediate angiography group and 165 of 258 patients (64.0%) in the delayed angiography group were alive (odds ratio, 0.90; 95% CI, 0.63-1.28). The composite end point of death, myocardial infarction, or repeated revascularization since the index hospitalization was met in 112 patients (42.9%) in the immediate group and 104 patients (40.6%) in the delayed group (odds ratio, 1.10; 95% CI, 0.77-1.56). No significant differences between the groups were observed for the other outcomes at 1-year follow-up. For example, the rate of ICD shocks was 20.4% in the immediate group and 16.2% in the delayed group (odds ratio, 1.32; 95% CI, 0.66-2.64).

Conclusions And Relevance: In this trial of patients successfully resuscitated after out-of-hospital cardiac arrest and without signs of STEMI, a strategy of immediate angiography was not found to be superior to a strategy of delayed angiography with respect to clinical outcomes at 1 year. Coronary angiography in this patient group can therefore be delayed until after neurologic recovery without affecting outcomes.

Trial Registration: trialregister.nl Identifier: NTR4973.
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http://dx.doi.org/10.1001/jamacardio.2020.3670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489423PMC
December 2020

Evaluation and Management of Nonculprit Lesions in STEMI.

JACC Cardiovasc Interv 2020 05;13(10):1145-1154

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Nonculprit lesions are frequently observed in patients with ST-segment elevation myocardial infarction. Results from recent randomized clinical trials suggest that complete revascularization after ST-segment elevation myocardial infarction improves outcomes. In this state-of-the-art paper, the authors review these trials and consider how best to determine which nonculprit lesions require revascularization and when this should be performed.
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http://dx.doi.org/10.1016/j.jcin.2020.02.030DOI Listing
May 2020

Platelet Inhibition, Endothelial Function, and Clinical Outcome in Patients Presenting With ST-Segment-Elevation Myocardial Infarction Randomized to Ticagrelor Versus Prasugrel Maintenance Therapy: Long-Term Follow-Up of the REDUCE-MVI Trial.

J Am Heart Assoc 2020 03 3;9(5):e014411. Epub 2020 Mar 3.

Department of Cardiology Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam Cardiovascular Sciences Amsterdam the Netherlands.

Background Off-target properties of ticagrelor might reduce microvascular injury and improve clinical outcome in patients with ST-segment-elevation myocardial infarction. The REDUCE-MVI (Evaluation of Microvascular Injury in Revascularized Patients with ST-Segment-Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel) trial reported no benefit of ticagrelor regarding microvascular function at 1 month. We now present the follow-up data up to 1.5 years. Methods and Results We randomized 110 patients with ST-segment-elevation myocardial infarction to either ticagrelor 90 mg twice daily or prasugrel 10 mg once a day. Platelet inhibition and peripheral endothelial function measurements including calculation of the reactive hyperemia index and clinical follow-up were obtained up to 1.5 years. Major adverse clinical events and bleedings were scored. An intention to treat and a per-protocol analysis were performed. There were no between-group differences in platelet inhibition and endothelial function. At 1 year the reactive hyperemia index in the ticagrelor group was 0.66±0.26 versus 0.61±0.28 in the prasugrel group (=0.31). Platelet inhibition was lower at 1 month versus 1 year in the total study population (61% [42%-81%] versus 83% [61%-95%]; <0.001), and per-protocol platelet inhibition was higher in patients randomized to ticagrelor versus prasugrel at 1 year (91% [83%-97%] versus 82% [65%-92%]; =0.002). There was an improvement in intention to treat endothelial function in patients randomized to ticagrelor (=0.03) but not in patients randomized to prasugrel (=0.88). Major adverse clinical events (10% versus 14%; =0.54) and bleedings (47% versus 63%; =0.10) were similar in the intention-to-treat analysis in both groups. Conclusions Platelet inhibition at 1 year was higher in the ticagrelor group, without an accompanying increase in bleedings. Endothelial function improved over time in ticagrelor patients, while it did not change in the prasugrel group. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique Identifier: NCT02422888.
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http://dx.doi.org/10.1161/JAHA.119.014411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335553PMC
March 2020

Downstream Influence of Coronary Stenoses on Microcirculatory Remodeling: A Histopathology Study.

Arterioscler Thromb Vasc Biol 2020 01 31;40(1):230-238. Epub 2019 Oct 31.

From the Department of Cardiology (G.A.d.W., M.R.H., D.R., T.t.B.H., R.M., N.W.v.d.H., N.v.R.), VU University Medical Center, Amsterdam, The Netherlands.

Objective: Inducible myocardial ischemia is influenced by contributions of both the epicardial artery and the coronary microcirculation. Experimental studies have found adverse microcirculatory remodeling to occur downstream of severe coronary stenoses. Coronary physiology studies in patients contradict the experimental findings, as the minimal microvascular resistance is not modified by stenoses. The objective was to determine whether microcirculatory remodeling occurs downstream of coronary stenoses in the human coronary circulation. Approach and Results: Myocardium corresponding to 115 coronary arteries of 55 deceased patients was investigated. Histopathologic staining of the microcirculation was performed using antibodies against SMA-α (smooth muscle actin-α) and CD31, to stain arterioles and capillaries, respectively. The following parameters were analyzed: ratio between lumen and vesel area, ratio between lumen and vessel diameter (both ratios for arterioles of <40, 40-100, and 100-200 µm diameter), arteriolar density, and capillary density. From the 55 patients, 32 pairs of an unobstructed coronary artery and a coronary artery with a stenosis were formed. No statistically significant differences between any of the microcirculatory parameters were found. A confirmatory unpaired analysis compared 3 groups: (1) coronary arteries in patients without coronary artery disease (n=53), (2) unobstructed coronary arteries in patients with a stenosis in one of the other coronary arteries (n=23), and (3) coronary stenoses (n=39). No statistically significant differences were observed between the groups.

Conclusions: The microcirculation distal to noncritical stenoses does not undergo structural remodeling in the human coronary circulation.
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http://dx.doi.org/10.1161/ATVBAHA.119.313462DOI Listing
January 2020

Cardiac Magnetic Resonance for Evaluating Nonculprit Lesions After Myocardial Infarction: Comparison With Fractional Flow Reserve.

JACC Cardiovasc Imaging 2020 03 18;13(3):715-728. Epub 2019 Sep 18.

Department of Cardiology, Amsterdam University Medical Centers, location VUmc, Amsterdam, the Netherlands; Department of Cardiology, Radboud University Medical Centers, Nijmegen, the Netherlands. Electronic address:

Objectives: This study sought to determine the agreement between cardiac magnetic resonance (CMR) imaging and invasive measurements of fractional flow reserve (FFR) in the evaluation of nonculprit lesions after ST-segment elevation myocardial infarction (STEMI). In addition, we investigated whether fully quantitative analysis of myocardial perfusion is superior to semiquantitative and visual analysis.

Background: The agreement between CMR and FFR in the evaluation of nonculprit lesions in patients with STEMI with multivessel disease is unknown.

Methods: Seventy-seven patients with STEMI with at least 1 intermediate (diameter stenosis 50% to 90%) nonculprit lesion underwent CMR and invasive coronary angiography in conjunction with FFR measurements at 1 month after primary intervention. The imaging protocol included stress and rest perfusion, cine imaging, and late gadolinium enhancement. Fully quantitative, semiquantitative, and visual analysis of myocardial perfusion were compared against a reference of FFR. Hemodynamically obstructive was defined as FFR ≤0.80.

Results: Hemodynamically obstructive nonculprit lesions were present in 31 (40%) patients. Visual analysis displayed an area under the curve (AUC) of 0.74 (95% confidence interval [CI]: 0.62 to 0.83), with a sensitivity of 73% and a specificity of 70%. For semiquantitative analysis, the relative upslope of the stress signal intensity time curve and the relative upslope derived myocardial flow reserve had respective AUCs of 0.66 (95% CI: 0.54 to 0.77) and 0.71 (95% CI: 0.59 to 0.81). Fully quantitative analysis did not augment diagnostic performance (all p > 0.05). Stress myocardial blood flow displayed an AUC of 0.76 (95% CI: 0.64 to 0.85), with a sensitivity of 69% and a specificity of 77%. Similarly, MFR displayed an AUC of 0.82 (95% CI: 0.71 to 0.90), with a sensitivity of 82% and a specificity of 71%.

Conclusions: CMR and FFR have moderate-good agreement in the evaluation of nonculprit lesions in patients with STEMI with multivessel disease. Fully quantitative, semiquantitative, and visual analysis yield similar diagnostic performance.
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http://dx.doi.org/10.1016/j.jcmg.2019.07.019DOI Listing
March 2020

1-Year Outcomes of Delayed Versus Immediate Intervention in Patients With Transient ST-Segment Elevation Myocardial Infarction.

JACC Cardiovasc Interv 2019 11 2;12(22):2272-2282. Epub 2019 Sep 2.

Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Objectives: The aim of the present study was to determine the effect of a delayed versus an immediate invasive approach on final infarct size and clinical outcome up to 1 year.

Background: Up to 24% of patients with acute coronary syndromes present with ST-segment elevation myocardial infarction (STEMI) but show complete resolution of ST-segment elevation and symptoms before revascularization. Current guidelines do not clearly state whether these patients with transient STEMI should be treated with a STEMI-like or non-ST-segment elevation acute coronary syndrome-like intervention strategy.

Methods: In this multicenter trial, 142 patients with transient STEMI were randomized 1:1 to either delayed or immediate coronary intervention. Cardiac magnetic resonance imaging was performed at 4 days and at 4-month follow-up to assess infarct size and myocardial function. Clinical follow-up was performed at 4 and 12 months.

Results: In the delayed (22.7 h) and the immediate (0.4 h) invasive groups, final infarct size as a percentage of the left ventricle was very small (0.4% [interquartile range: 0.0% to 2.5%] vs. 0.4% [interquartile range: 0.0% to 3.5%]; p = 0.79), and left ventricular function was good (mean ejection fraction 59.3 ± 6.5% vs. 59.9 ± 5.4%; p = 0.63). In addition, the overall occurrence of major adverse cardiac events, consisting of death, recurrent infarction, and target lesion revascularization, up to 1 year was low and not different between both groups (5.7% vs. 4.4%, respectively; p = 1.00).

Conclusions: At follow-up, patients with transient STEMI have limited infarction and well-preserved myocardial function in general, and delayed or immediate revascularization has no effect on functional outcome and clinical events up to 1 year.
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http://dx.doi.org/10.1016/j.jcin.2019.07.018DOI Listing
November 2019

Interindividual Variations in the Adenosine-Induced Hemodynamics During Fractional Flow Reserve Evaluation: Implications for the Use of Quantitative Flow Ratio in Assessing Intermediate Coronary Stenoses.

J Am Heart Assoc 2019 08 9;8(16):e012906. Epub 2019 Aug 9.

Hospital Clínico San Carlos IDISSC and Universidad Complutense de Madrid Spain.

Background Quantitative flow ratio (QFR), a novel functional angiography technique, computes fractional flow reserve (FFR) without pressure wires or adenosine. We investigated interindividual variations in the adenosine-induced hemodynamics during FFR assessment and their influence on QFR diagnostic performance. Methods and Results Patients with coronary stenoses who underwent intracoronary pressure and flow assessment were analyzed. Adenosine-induced hemodynamics during FFR measurement were determined by the percentage change in mean aortic pressure (%ΔPa) and the resistive reserve ratio (RRR). The diagnostic performance of QFR was evaluated and compared in each tertile of %ΔPa and RRR using FFR as reference. A total of 294 vessels (245 patients) were analyzed. Mean FFR was 0.80±0.11. Individuals showed a wide variation in the adenosine response in terms of %ΔPa (ranging from -75% to 43%; median, -9% [interquartile range, -3% to -17%]) and the RRR (ranging from 0.45 to 20.15; median, 3.1 [interquartile range, 2.1-4.9]). No significant differences for diagnostic efficiency of QFR were found between tertiles of %ΔPa (area under the curve for the receiver-operating characteristic analysis, 0.950 in tertile 1, 0.929 in tertile 2, and 0.910 in tertile 3; P=0.270) or between tertiles of the RRR (area under the curve for the receiver-operating characteristic analysis, 0.909 in tertile 1, 0.923 in tertile 2, and 0.959 in tertile 3; P=0.167). The classification agreement between QFR and FFR was not significantly modified by %ΔPa (tertile 1, 89%; tertile 2, 87%; and tertile 3, 86%; P=0.827) or by the RRR (tertile 1, 86%; tertile 2, 85%; and tertile 3, 91%; P=0.398). Conclusions Patients undergoing FFR assessment show large interindividual variations in the magnitude of adenosine-induced hemodynamics. However, such variations do not affect the diagnostic performance of QFR in assessing the functional relevance of observed stenoses.
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http://dx.doi.org/10.1161/JAHA.119.012906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759899PMC
August 2019

Temporal Changes in Coronary Hyperemic and Resting Hemodynamic Indices in Nonculprit Vessels of Patients With ST-Segment Elevation Myocardial Infarction.

JAMA Cardiol 2019 08;4(8):736-744

Department of Cardiology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.

Importance: Percutaneous coronary intervention (PCI) of nonculprit vessels among patients with ST-segment elevation myocardial infarction (STEMI) is associated with improved clinical outcome compared with culprit vessel-only PCI. Fractional flow reserve (FFR) and coronary flow reserve are hyperemic indices used to guide revascularization. Recently, instantaneous wave-free ratio was introduced as a nonhyperemic alternative to FFR. Whether these indices can be used in the acute setting of STEMI continues to be investigated.

Objective: To assess the value of hemodynamic indices in nonculprit vessels of patients with STEMI from the index event to 1-month follow-up.

Design, Setting, And Participants: This substudy of the Reducing Micro Vascular Dysfunction in Revascularized STEMI Patients by Off-target Properties of Ticagrelor (REDUCE-MVI) randomized clinical trial enrolled 98 patients with STEMI who had an angiographic intermediate stenosis in at least 1 nonculprit vessel. Patient enrollment was between May 1, 2015, and September 19, 2017. After successful primary PCI, nonculprit intracoronary hemodynamic measurements were performed and repeated at 1-month follow-up. Cardiac magnetic resonance imaging was performed from 2 to 7 days and 1 month after primary PCI.

Main Outcomes And Measures: The value of nonculprit instantaneous wave-free ratio, FFR, coronary flow reserve, hyperemic index of microcirculatory resistance, and resting microcirculatory resistance from the index event to 1-month follow-up.

Results: Of 73 patients with STEMI included in the final analysis, 59 (80.8%) were male, with a mean (SD) age of 60.8 (9.9) years. Instantaneous wave-free ratio (SD) did not change significantly (0.93 [0.07] vs 0.94 [0.06]; P = .12) and there was no change in resting distal pressure/aortic pressure (mean [SD], 0.94 [0.06] vs 0.95 [0.06]; P = .25) from the acute moment to 1-month follow-up. The FFR decreased (mean [SD], 0.88 [0.07] vs 0.86 [0.09]; P = .001) whereas coronary flow reserve increased (mean [SD], 2.9 [1.4] vs 4.1 [2.2]; P < .001). Hyperemic index of microcirculatory resistance decreased and resting microcirculatory resistance increased from the acute moment to follow-up. The decrease in distal pressure from rest to hyperemia was smaller at the acute moment vs follow-up (mean [SD], 10.6 [11.2] mm Hg vs 14.1 [14.2] mm Hg; P = .05). This blunted acute hyperemic response correlated with final infarct size (ρ, -0.29; P = .02). The resistive reserve ratio was lower at the acute moment vs follow-up (mean [SD], 3.4 [1.7] vs 5.0 [2.7]; P < .001).

Conclusions And Relevance: In the acute setting of STEMI, nonculprit coronary flow reserve was reduced and FFR was augmented, whereas instantaneous wave-free ratio was not altered. These results may be explained by an increased hyperemic microvascular resistance and a blunted adenosine responsiveness at the acute moment that was associated with infarct size.
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http://dx.doi.org/10.1001/jamacardio.2019.2138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613339PMC
August 2019

Acute-onset coma after iso-osmolar iodinated contrast injection: a case report of contrast-induced encephalopathy after elective coronary angiography.

Eur Heart J Case Rep 2018 Dec 27;2(4):yty132. Epub 2018 Nov 27.

Department of Cardiology, VU University Medical Center, De Boelelaan 1117, HV Amsterdam, The Netherlands.

Background: Contrast-induced encephalopathy (CIE) is a rare complication of coronary angiography (CAG) caused by a direct neurotoxic reaction to iodinated contrast medium. Contrast-induced encephalopathy can result in a variety of neurological symptoms following within minutes to hours after contrast injection. It manifests most frequently as transient cortical blindness, headache, or confusion. In the majority of known cases, symptoms completely resolve solely with supportive care. We present a case where CIE takes a more dramatic course.

Case Summary: A 67-year-old woman was scheduled for elective CAG, due to progressive typical chest pain. Within minutes after injection of iso-osmolar iodinated contrast medium, the patient showed a sudden decline in consciousness while all other vital functions remained normal. Shortly, after the patient was admitted to the intensive care unit due to acute-onset coma and respiratory insufficiency. A computed tomography scan of the brain showed bilateral cerebral oedema, which in combination with the development of symptoms after contrast injection led to the diagnosis of CIE. Remarkable decrease of cerebral oedema was observed 1 day later and slowly clinical recovery ensued. After 23 days, the patient was discharged from the cardiology ward. Follow-up at the outpatient clinic showed no lasting neurological deficits.

Discussion:  While most symptoms of CIE are relatively mild and transient in nature, we describe a more devastating course that occurred with the use of only a low quantity of iso-osmolar contrast medium. We emphasize that even the more severe manifestations of CIE can develop at any dosage, and with all types of iodinated contrast medium.
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http://dx.doi.org/10.1093/ehjcr/yty132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426011PMC
December 2018

Coronary Microcirculation Downstream Non-Infarct-Related Arteries in the Subacute Phase of Myocardial Infarction: Implications for Physiology-Guided Revascularization.

J Am Heart Assoc 2019 05;8(9):e011534

1 Hospital Clínico San Carlos IDISSC and Universidad Complutense de Madrid Madrid Spain.

Background Concerns exist about reliability of pressure-wire-guided coronary revascularization of non-infarct-related arteries (non- IRA ). We investigated whether physiological assessment of non- IRA during the subacute phase of myocardial infarction might be flawed by microcirculatory dysfunction. Methods and Results We analyzed non- IRA that underwent fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance assessment. Microcirculation and hyperemic response were evaluated in 49 acute myocardial infarction patients (59 non- IRA ) and compared with a matched control group of 46 stable angina ( SA ) patients (59 vessels). Time between acute myocardial infarction to physiological interrogation was 5.9±2.4 days. Fractional flow reserve was similar in both groups (0.79±0.11 in non- IRA versus 0.80±0.13 in SA vessels, P=0.527). Lower coronary flow reserve values were found in non- IRA compared with SA vessels (1.77 [1.25-2.76] versus 2.44 [1.63-4.00], P=0.018), primarily driven by an increased baseline flow in non- IRA (rest mean transit time 0.58 [0.32-0.83] versus 0.65 s [0.39-1.20], P=0.045), whereas the hyperemic flow was similar (hyperemic mean transit time 0.26 [0.20-0.42] versus 0.26 s [0.18-0.35], P=0.873). No differences were found regarding index of microcirculatory resistance (15.6 [10.4-21.8] in non- IRA versus 16.7 [11.6-23.6] U in SA vessels, P=0.559). During adenosine infusion, the hyperemic response was similar in both groups (non- IRA versus SA vessels) in terms of the resistive reserve ratio (3.1±2.1 versus 3.7±2.2, P=0.118). Conclusions In the subacute phase of myocardial infarction, non- IRA show an increased baseline flow that may cause abnormal coronary flow reserve despite preserved hyperemic flow. In non- IRA , microcirculatory resistance and adenosine-induced hyperemic response are similar to those found in SA patients. From a physiological perspective, these findings support the use of fractional flow reserve to interrogate non- IRA during the subacute phase of myocardial infarction.
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http://dx.doi.org/10.1161/JAHA.118.011534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512122PMC
May 2019

Diastolic-systolic velocity ratio to detect coronary stenoses under physiological resting conditions: a mechanistic study.

Open Heart 2019;6(1):e000968. Epub 2019 Mar 1.

Imperial College London, London, UK.

Objective: Diastolic-systolic velocity ratio (DSVR) is a resting index to assess stenoses in the left anterior descending artery (LAD). DSVR can be measured by echocardiographic or intracoronary Doppler flow velocity. The objective of this cohort study was to elucidate the fundamental rationale underlying the decreased DSVR in coronary stenoses.

Methods: In cohort 1, simultaneous measurements of intracoronary Doppler flow velocity and pressure were acquired in the LAD of 228 stable patients. Phasic stenosis resistance, microvascular resistance and total vascular resistance (defined as stenosis and microvascular resistance combined) were studied during physiological resting conditions. Stenoses were classified according to severity by strata of 0.10 fractional flow reserve (FFR) units.

Results: DSVR was decreased in stenoses with lower FFR. Stenosis resistance was equal in systole and diastole for every FFR stratum. Microvascular resistance was consistently higher during systole than diastole. In lower FFR strata, stenosis resistance as a percentage of the total vascular resistance increases both during systole and diastole. The difference between the stenosis resistance as a percentage of total vascular resistance during systole and diastole increases for lower FFR strata, with an accompanying rise in diastolic-systolic resistance ratio. A significant inverse correlation was observed between DSVR and the diastolic-systolic resistance ratio (r=0.91, p<0.001). In cohort 2 (n=23), DSVR was measured both invasively and non-invasively by transthoracic echocardiography, yielding a good correlation (r=0.82, p<0.001).

Conclusions: The rationale by which DSVR is decreased distal to coronary stenoses is dependent on a comparatively higher influence of the increased stenosis resistance on total vascular resistance during diastole than systole.
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http://dx.doi.org/10.1136/openhrt-2018-000968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443135PMC
February 2021

Quantitative flow ratio for immediate assessment of nonculprit lesions in patients with ST-segment elevation myocardial infarction-An iSTEMI substudy.

Catheter Cardiovasc Interv 2019 Nov 25;94(5):686-692. Epub 2019 Mar 25.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Objectives: We evaluated the diagnostic performance of quantitative flow ratio (QFR) assessment of nonculprit lesions (NCLs) based on acute setting angiograms obtained in patients with ST-segment elevation myocardial infarction (STEMI) with QFR, fractional flow reserve (FFR), and instantaneous wave-free ratio (iFR) in the staged setting as reference.

Background: QFR is an angiography-based approach for the functional evaluation of coronary artery lesions.

Methods: This was a post-hoc analysis of the iSTEMI study. NCLs were assessed with iFR in the acute setting and with iFR and FFR at staged (median 13 days) follow-up. Acute and staged QFR values were computed in a core laboratory based on the coronary angiography recordings. Diagnostic cut-off values were ≤0.80 for QFR and FFR, and ≤0.89 for iFR.

Results: Staged iFR and FFR data were available for 146 NCLs in 112 patients in the iSTEMI study. Among these, QFR analysis was feasible in 103 (71%) lesions assessed in the acute setting with a mean QFR value of 0.82 (IQR: 0.73-0.91). Staged QFR, FFR, and iFR were 0.80 (IQR: 0.70-0.90), 0.81 (IQR: 0.71-0.88), and 0.91 (IQR: 0.87-0.96), respectively. Classification agreement of acute and staged QFR was 93% (95%Cl: 87-99). The classification agreement of acute QFR was 84% (95%CI: 76-90) using staged FFR as reference and 74% (95%CI: 65-83) using staged iFR as reference.

Conclusions: Acute QFR showed a very good diagnostic performance with staged QFR as reference, a good diagnostic performance with staged FFR as reference, and a moderate diagnostic performance with staged iFR as reference.
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http://dx.doi.org/10.1002/ccd.28208DOI Listing
November 2019

Coronary Angiography after Cardiac Arrest without ST-Segment Elevation.

N Engl J Med 2019 Apr 18;380(15):1397-1407. Epub 2019 Mar 18.

From the Departments of Cardiology (J.S.L., G.N.J., N.W.H., N.R.), Intensive Care Medicine (P.W.G.E., H.M.O.-S.), and Epidemiology and Biostatistics (P.M.V.), Amsterdam University Medical Center VUmc, the Departments of Cardiology (J.P.H.) and Intensive Care Medicine (A.P.J.V.), Amsterdam University Medical Center AMC, and the Departments of Cardiology (M.A.V.) and Intensive Care Medicine (B.B.), Onze Lieve Vrouwe Gasthuis, Amsterdam, the Thorax Center, Erasmus Medical Center (L.S.D.J., E.A.D.), and the Departments of Cardiology (G.J.V.) and Intensive Care Medicine (B.J.W.E.), Maasstad Hospital, Rotterdam, the Departments of Cardiology (M. Meuwissen) and Intensive Care Medicine (T.A.R.), Amphia Hospital, Breda, the Departments of Cardiology (H.A.B.) and Intensive Care Medicine (M.J.B.), Rijnstate Hospital, Arnhem, the Departments of Cardiology (G.B.B.) and Intensive Care Medicine (R.B.), Haga Hospital, and the Department of Cardiology, Haaglanden Medical Center (P.V.O.), The Hague, the Departments of Cardiology (P.H.) and Intensive Care Medicine (I.C.C.H.), University of Groningen, Groningen, the Departments of Cardiology (M.V.) and Intensive Care Medicine (J.J.H.), University Medical Center Utrecht, Utrecht, the Departments of Intensive Care Medicine (A.B.) and Cardiology (M.S.), Medisch Spectrum Twente, Enschede, the Departments of Cardiology (C.C., N.R.) and Intensive Care Medicine (H.H.), Radboud University Medical Center, Nijmegen, the Departments of Cardiology (T.A.C.M.H.) and Intensive Care Medicine (W.R.), Noordwest Ziekenhuisgroep, Alkmaar, the Departments of Intensive Care Medicine (T.S.R.D.) and Cardiology (H.J.G.M.C.), Maastricht University Medical Center, Maastricht, the Department of Cardiology, Scheper Hospital, Emmen (G.A.J.J.), the Department of Cardiology, Isala Hospital, Zwolle (M.T.M.G.), the Department of Cardiology, Tergooi Hospital, Blaricum (K.P.), and the Department of Cardiology, Elisabeth-Tweesteden Hospital, Tilburg (M. Magro) - all in the Netherlands.

Background: Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography and percutaneous coronary intervention (PCI) in the treatment of patients who have been successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains uncertain.

Methods: In this multicenter trial, we randomly assigned 552 patients who had cardiac arrest without signs of STEMI to undergo immediate coronary angiography or coronary angiography that was delayed until after neurologic recovery. All patients underwent PCI if indicated. The primary end point was survival at 90 days. Secondary end points included survival at 90 days with good cerebral performance or mild or moderate disability, myocardial injury, duration of catecholamine support, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, major bleeding, occurrence of acute kidney injury, need for renal-replacement therapy, time to target temperature, and neurologic status at discharge from the intensive care unit.

Results: At 90 days, 176 of 273 patients (64.5%) in the immediate angiography group and 178 of 265 patients (67.2%) in the delayed angiography group were alive (odds ratio, 0.89; 95% confidence interval [CI], 0.62 to 1.27; P = 0.51). The median time to target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group (ratio of geometric means, 1.19; 95% CI, 1.04 to 1.36). No significant differences between the groups were found in the remaining secondary end points.

Conclusions: Among patients who had been successfully resuscitated after out-of-hospital cardiac arrest and had no signs of STEMI, a strategy of immediate angiography was not found to be better than a strategy of delayed angiography with respect to overall survival at 90 days. (Funded by the Netherlands Heart Institute and others; COACT Netherlands Trial Register number, NTR4973.).
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http://dx.doi.org/10.1056/NEJMoa1816897DOI Listing
April 2019

Evaluation of Microvascular Injury in Revascularized Patients With ST-Segment-Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel.

Circulation 2019 01;139(5):636-646

Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands (M.A.H.v.L., N.W.v.d.H., G.N.J., H.E., A.N., J.S.L., G.A.d.W., A.C.v.R., R.N., N.v.R.).

Background: Despite successful restoration of epicardial vessel patency with primary percutaneous coronary intervention, coronary microvascular injury occurs in a large proportion of patients with ST-segment-elevation myocardial infarction, adversely affecting clinical and functional outcome. Ticagrelor has been reported to increase plasma adenosine levels, which might have a protective effect on the microcirculation. We investigated whether ticagrelor maintenance therapy after revascularized ST-segment-elevation myocardial infarction is associated with less coronary microvascular injury compared to prasugrel maintenance therapy.

Methods: A total of 110 patients with ST-segment-elevation myocardial infarction received a loading dose of ticagrelor and were randomized to maintenance therapy of ticagrelor (n=56) or prasugrel (n=54) after primary percutaneous coronary intervention. The primary outcome was coronary microvascular injury at 1 month, as determined with the index of microcirculatory resistance in the infarct-related artery. Cardiovascular magnetic resonance imaging was performed during the acute phase and at 1 month.

Results: The primary outcome of index of microcirculatory resistance was not superior in ticagrelor- or prasugrel-treated patients (ticagrelor, 21 [interquartile range, 15-39] U; prasugrel, 18 [interquartile range, 11-29] U; P=0.08). Recovery of microcirculatory resistance over time was not better in patients with ticagrelor versus prasugrel (ticagrelor, -13.9 U; prasugrel, -13.5 U; P=0.96). Intramyocardial hemorrhage was observed less frequently in patients receiving ticagrelor (23% versus 43%; P=0.04). At 1 month, no difference in infarct size was observed (ticagrelor, 7.6 [interquartile range, 3.7-14.4] g, prasugrel 9.9 [interquartile range, 5.7-16.6] g; P=0.17). The occurrence of microvascular obstruction was not different in patients on ticagrelor (28%) or prasugrel (41%; P=0.35). Plasma adenosine concentrations were not different during the index procedure and during maintenance therapy with ticagrelor or prasugrel.

Conclusions: In patients with ST-segment-elevation myocardial infarction, ticagrelor maintenance therapy was not superior to prasugrel in preventing coronary microvascular injury in the infarct-related territory as assessed by the index of microcirculatory resistance, and this resulted in a comparable infarct size at 1 month.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02422888.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035931DOI Listing
January 2019

Timing of revascularization in patients with transient ST-segment elevation myocardial infarction: a randomized clinical trial.

Eur Heart J 2019 01;40(3):283-291

Department of Cardiology, Amsterdam UMC, VU University Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands.

Aims: Patients with acute coronary syndrome who present initially with ST-elevation on the electrocardiogram but, subsequently, show complete normalization of the ST-segment and relief of symptoms before reperfusion therapy are referred to as transient ST-segment elevation myocardial infarction (STEMI) and pose a therapeutic challenge. It is unclear what the optimal timing of revascularization is for these patients and whether they should be treated with a STEMI-like or a non-ST-segment elevation myocardial infarction (NSTEMI)-like invasive approach. The aim of the study is to determine the effect of an immediate vs. a delayed invasive strategy on infarct size measured by cardiac magnetic resonance imaging (CMR).

Methods And Results: In a randomized clinical trial, 142 patients with transient STEMI with symptoms of any duration were randomized to an immediate (STEMI-like) [0.3 h; interquartile range (IQR) 0.2-0.7 h] or a delayed (NSTEMI-like) invasive strategy (22.7 h; IQR 18.2-27.3 h). Infarct size as percentage of the left ventricular myocardial mass measured by CMR at day four was generally small and not different between the immediate and the delayed invasive group (1.3%; IQR 0.0-3.5% vs. 1.5% IQR 0.0-4.1%, P = 0.48). By intention to treat, there was no difference in major adverse cardiac events (MACE), defined as death, reinfarction, or target vessel revascularization at 30 days (2.9% vs. 2.8%, P = 1.00). However, four additional patients (5.6%) in the delayed invasive strategy required urgent intervention due to signs and symptoms of reinfarction while awaiting angiography.

Conclusion: Overall, infarct size in transient STEMI is small and is not influenced by an immediate or delayed invasive strategy. In addition, short-term MACE was low and not different between the treatment groups.
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http://dx.doi.org/10.1093/eurheartj/ehy651DOI Listing
January 2019

Comprehensive physiological evaluation of epicardial and microvascular coronary domains using vascular conductance and zero flow pressure.

EuroIntervention 2019 Feb 8;14(15):e1593-e1600. Epub 2019 Feb 8.

Department of Cardiology, VU University Medical Center, Amsterdam, the Netherlands.

Aims: Assessment of the coronary circulation has been based largely on pressure ratios (epicardial) and resistance (micro-vessels). Simultaneous assessment of epicardial (CEPI) and microvascular conductance (CMICRO) provides an intuitive approach using the same units for both coronary domains and expressing the actual deliverability of blood. The aim of this study was to develop a novel integral method for assessing the functional severity of epicardial and microvascular disease.

Methods And Results: We performed intracoronary pressure and Doppler flow velocity measurements in 403 vessels in 261 patients with stable coronary artery disease. Hyperaemic mid-to-late diastolic pressure and flow velocity (PV) relationships were calculated. The slope of the aortic PV indicates the overall conductance and the slope of the distal PV relationship represents CMICRO. The intercept with the x-axis represents zero-flow pressure (Pzf). CEPI was derived from microvascular and overall conductance. Median CEPI was higher compared to CMICRO (4.2 [2.1-8.0] versus 1.3 [1.0-1.7] cm/s/mmHg, p<0.001). CMICRO was independent of stenosis severity (1.3 [1.0-1.7] in FFR ≤0.80 versus 1.4 [1.0-1.8] in FFR >0.8, p=0.797). ROC curves (using FFR and HSR concordant vessels as standard) demonstrated an excellent ability of CEPI to characterise significant stenoses (AUC 0.93). When CEPI
Conclusions: A comprehensive assessment of separate CEPI and CMICRO was feasible. CEPI has a remarkable diagnostic efficiency to detect a clinically relevant stenosis. When CEPI
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http://dx.doi.org/10.4244/EIJ-D-18-00021DOI Listing
February 2019

Influence of Microcirculatory Dysfunction on Angiography-Based Functional Assessment of Coronary Stenoses.

JACC Cardiovasc Interv 2018 04;11(8):741-753

Department of Cardiology, Hospital Clínico San Carlos IDISSC and Universidad Complutense de Madrid, Madrid, Spain. Electronic address:

Objectives: The authors sought to evaluate the influence of coronary microcirculatory dysfunction (CMD) on the diagnostic performance of the quantitative flow ratio (QFR).

Background: Functional angiographic assessment of coronary stenoses based on fluid dynamics, such as QFR, constitutes an attractive alternative to fractional flow reserve (FFR). However, it is unknown whether CMD affects the reliability of angiography-based functional indices.

Methods: FFR and the index of microcirculatory resistance (IMR) were measured in 300 vessels (248 patients) as part of a multicenter international registry. QFR was calculated at a blinded core laboratory. Vessels were classified into 2 groups according to microcirculatory status: low IMR (<23 U), and high IMR (≥23 U, CMD). The impact of CMD on the diagnostic performance of QFR, as well as on incremental value of QFR over quantitative angiography, was assessed using FFR as reference.

Results: Percent diameter stenosis (%DS) and FFR were similar in low- and high-IMR groups (%DS 51 ± 12% vs. 53 ± 11%; p = 0.16; FFR 0.80 ± 0.11 vs. 0.81 ± 0.11; p = 0.23, respectively). In the overall cohort, classification agreement (CA) between QFR and FFR and diagnostic efficiency of QFR (area under the receiver-operating characteristics curve [AUC]) were high (CA: 88%; AUC: 0.93 [95% confidence interval (CI): 0.90 to 0.96]). However, when assessed according to microcirculatory status, a significantly lower CA and AUC of QFR were found in the high-IMR group as compared with the low-IMR group (CA: 76% vs. 92%; p < 0.001; AUC: 0.88 [95% CI: 0.79 to 0.94] vs. 0.96 [95% CI: 0.92 to 0.98]; p < 0.05). Compared with angiographic assessment, QFR increased by 0.20 (p < 0.001) and by 0.16 (p < 0.001) the AUC of %DS in low- and high-IMR groups, respectively. Independent predictors of misclassification between QFR and FFR were high IMR and acute coronary syndrome.

Conclusions: CMD decreases the diagnostic performance of QFR. However, even in the presence of CMD, QFR remains superior to angiography alone in ascertaining functional stenosis severity.
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http://dx.doi.org/10.1016/j.jcin.2018.02.014DOI Listing
April 2018

Bivalirudin infusion to reduce ventricular infarction: the open-label, randomised Bivalirudin Infusion for Ventricular InfArction Limitation (BIVAL) study.

EuroIntervention 2017 Aug 4;13(5):e540-e548. Epub 2017 Aug 4.

Erasmus MC, Rotterdam, the Netherlands.

Aims: The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI).

Methods And Results: This multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0±19.7 g for bivalirudin vs. 27.1±20.7 g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8 g vs. 7.7±6.3 g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility.

Conclusions: This study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.
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http://dx.doi.org/10.4244/EIJ-D-17-00307DOI Listing
August 2017

Coronary angiography and percutaneous coronary intervention after out-of-hospital cardiac arrest: major leaps towards improved survival?

J Thorac Dis 2017 Jan;9(1):5-7

Department of Cardiology, Institute of Cardiovascular Research ICaR-VU, VU University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.21037/jtd.2017.01.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303092PMC
January 2017

Invasive minimal Microvascular Resistance Is a New Index to Assess Microcirculatory Function Independent of Obstructive Coronary Artery Disease.

J Am Heart Assoc 2016 12 22;5(12). Epub 2016 Dec 22.

VU University Medical Center, Amsterdam, The Netherlands

Background: Coronary microcirculatory dysfunction portends a poor cardiovascular outcome. Invasive assessment of microcirculatory dysfunction by coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) is affected by coronary artery disease (CAD). In this study we propose minimal microvascular resistance (mMR) as a new measure of microcirculatory dysfunction and aim to determine whether mMR is influenced by CAD.

Methods And Results: We obtained 482 simultaneous measurements of intracoronary Doppler flow velocity and pressure. The mMR is defined as the ratio between distal coronary pressure and flow velocity during the hyperemic wave-free period. Measurements were divided into 2 cohorts. Cohort 1 was a paired analysis involving 81 pairs with a vessel with and without CAD to investigate whether HMR, CFR, and mMR are modulated by CAD. CFR was lower, and HMR was higher, in vessels with CAD than in vessels without CAD: 2.12±0.79 versus 2.56±0.63 mm Hg·cm·s, P<0.001, and 2.61±1.22 versus 2.31±0.89 mm Hg·cm·s, P=0.04, respectively. mMR was equal in vessels with and without CAD: 1.54±0.77 versus 1.53±0.57 mm Hg·cm·s, P=0.90. Differences for CFR occurred when FFR was 0.60 to 0.80 or ≤0.60 but not when FFR ≥0.80. For HMR, the difference occurred only when FFR ≤0.60. For mMR, no difference was observed in any FFR stratum. Cohort 2 was used for validation and showed significant relationships for CFR and HMR with FFR: Pearson r=0.488, P<0.001 and -0.159, P=0.03, respectively; mMR had no association with FFR: Pearson r=0.055; P=0.32.

Conclusions: mMR is a novel index to assess microcirculatory dysfunction and is not modified by the presence of obstructive CAD.
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http://dx.doi.org/10.1161/JAHA.116.004482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210399PMC
December 2016

Coronary angiography after cardiac arrest: Rationale and design of the COACT trial.

Am Heart J 2016 Oct 14;180:39-45. Epub 2016 Jul 14.

Department of Cardiology, VU University Medical Centre, Amsterdam, the Netherlands.

Background: Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography (CAG) and percutaneous coronary intervention (PCI) after restoration of spontaneous circulation following cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains debated.

Hypothesis: We hypothesize that immediate CAG and PCI, if indicated, will improve 90-day survival in post-cardiac arrest patients without signs of STEMI.

Design: In a prospective, multicenter, randomized controlled clinical trial, 552 post-cardiac arrest patients with restoration of spontaneous circulation and without signs of STEMI will be randomized in a 1:1 fashion to immediate CAG and PCI (within 2 hours) versus initial deferral with CAG and PCI after neurological recovery. The primary end point of the study is 90-day survival. The secondary end points will include 90-day survival with good cerebral performance or minor/moderate disability, myocardial injury, duration of inotropic support, occurrence of acute kidney injury, need for renal replacement therapy, time to targeted temperature control, neurological status at intensive care unit discharge, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, and reasons for discontinuation of treatment.

Summary: The COACT trial is a multicenter, randomized, controlled clinical study that will evaluate the effect of an immediate invasive coronary strategy in post-cardiac arrest patients without STEMI on 90-day survival.
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http://dx.doi.org/10.1016/j.ahj.2016.06.025DOI Listing
October 2016

Reducing Microvascular Dysfunction in Revascularized Patients with ST-Elevation Myocardial Infarction by Off-Target Properties of Ticagrelor versus Prasugrel. Rationale and Design of the REDUCE-MVI Study.

J Cardiovasc Transl Res 2016 06 21;9(3):249-256. Epub 2016 Apr 21.

Department of Cardiology, Institute of Cardiovascular Research ICaR-VU, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Microvascular injury is present in a large proportion of patients with ST-elevation myocardial infarction (STEMI) despite successful revascularization. Ticagrelor potentially mitigates this process by exerting additional adenosine-mediated effects. This study aims to determine whether ticagrelor is associated with a better microvascular function compared to prasugrel as maintenance therapy after STEMI. A total of 110 patients presenting with STEMI and additional intermediate stenosis in another coronary artery will be studied after successful percutaneous coronary intervention (PCI) of the infarct-related artery. Patients will be randomized to treatment with ticagrelor or prasugrel for 1 year. FFR-guided PCI of the non-infarct-related artery will be performed at 1 month. Microvascular function will be assessed by measurement of the index of microcirculatory resistance (IMR) in the infarct-related artery and non-infarct-related artery, immediately after primary PCI and after 1 month. The REDUCE-MVI study will establish whether ticagrelor as a maintenance therapy may improve microvascular function in patients after revascularized STEMI.
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http://dx.doi.org/10.1007/s12265-016-9691-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873532PMC
June 2016

The emerging role of galectins in cardiovascular disease.

Vascul Pharmacol 2016 06 2;81:31-41. Epub 2016 Mar 2.

Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address:

Galectins are an ancient family of β-galactoside-specific lectins and consist of 15 different types, each with a specific function. They play a role in the immune system, inflammation, wound healing and carcinogenesis. In particular the role of galectin in cancer is widely studied. Lately, the role of galectins in the development of cardiovascular disease has gained attention. Worldwide cardiovascular disease is still the leading cause of death. In ischemic heart disease, atherosclerosis limits adequate blood flow. Angiogenesis and arteriogenesis are highly important mechanisms relieving ischemia by restoring perfusion to the post-stenotic myocardial area. Galectins act ambiguous, both relieving ischemia and accelerating atherosclerosis. Atherosclerosis can ultimately lead to myocardial infarction or ischemic stroke, which are both associated with galectins. There is also a role for galectins in the development of myocarditis by their influence on inflammatory processes. Moreover, galectin acts as a biomarker for the severity of myocardial ischemia and heart failure. This review summarizes the association between galectins and the development of multiple cardiovascular diseases such as myocarditis, ischemic stroke, myocardial infarction, heart failure and atrial fibrillation. Furthermore it focuses on the association between galectin and more general mechanisms such as angiogenesis, arteriogenesis and atherosclerosis.
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http://dx.doi.org/10.1016/j.vph.2016.02.006DOI Listing
June 2016
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