Publications by authors named "Bart Mertens"

84 Publications

Validation and Feasibility of Echocardiographic Assessment of Systemic Right Ventricular Function: Serial Correlation With MRI.

Front Cardiovasc Med 2021 16;8:644193. Epub 2021 Mar 16.

Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.

Inherent to its geometry, echocardiographic imaging of the systemic right ventricle (RV) is challenging. Therefore, echocardiographic assessment of systemic RV function may not always be feasible and/or reproducible in daily practice. Here, we aim to validate the usefulness of a comprehensive range of 32 echocardiographic measurements of systemic RV function in a longitudinal cohort by serial assessment of their correlations with cardiac magnetic resonance (CMR)-derived systemic RV ejection fraction (RVEF). A single-center, retrospective cohort study was performed. Adult patients with a systemic RV who underwent a combination of both CMR and echocardiography at two different points in time were included. Off-line analysis of echocardiographic images was blinded to off-line CMR analysis and vice versa. In half of the echocardiograms, measurements were repeated by a second observer blinded to the results of the first. Correlations between echocardiographic and CMR measures were assessed with Pearson's correlation coefficient and interobserver agreement was quantified with intraclass correlation coefficients (ICC). Fourteen patients were included, of which 4 had congenitally corrected transposition of the great arteries (ccTGA) and 10 patients had TGA late after an atrial switch operation. Eight patients (57%) were female. There was a mean of 8 years between the first and second imaging assessment. Only global systemic RV function, fractional area change (FAC), and global longitudinal strain (GLS) were consistently, i.e., at both time points, correlated with CMR-RVEF (global RV function: = -0.77/ = -0.63; FAC: = 0.79/ = 0.67; GLS: = -0.73/ = -0.70, all -values < 0.05). The ICC of GLS (0.82 at = 1, = 0.006, 0.77 at = 2, = 0.024) was higher than the ICC of FAC (0.35 at = 1, = 0.196, 0.70 at = 2, = 0.051) at both time points. GLS appears to be the most robust echocardiographic measurement of systemic RV function with good correlation with CMR-RVEF and reproducibility.
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http://dx.doi.org/10.3389/fcvm.2021.644193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008818PMC
March 2021

Mitral valve repair for isolated posterior mitral valve leaflet prolapse: The effect of respect and resect techniques on left ventricular function.

J Thorac Cardiovasc Surg 2021 Feb 23. Epub 2021 Feb 23.

Division of Cardiothoracic Surgeons, Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Objective: Posterior mitral valve leaflet prolapse repair can be performed by leaflet resection or chordal replacement techniques. The impact of these techniques on left ventricular function remains a topic of debate, considering the presumed better preservation of mitral-ventricular continuity when leaflet resection is avoided. We explored the effect of different posterior mitral valve leaflet repair techniques on postoperative left ventricular function.

Methods: In total, 125 patients were included and divided into 2 groups: leaflet resection (n = 82) and isolated chordal replacement (n = 43). Standard and advanced echocardiographic assessments were performed preoperatively, directly postoperatively, and at late follow-up. In addition, left ventricular global longitudinal strain was measured and corrected for left ventricular end-diastolic volume to adjust for the significant changes in left ventricular volumes.

Results: At baseline, no significant intergroup difference in left ventricular function was observed measured with the corrected left ventricular global longitudinal strain (resect: 1.76% ± 0.58%/10 mL vs respect: 1.70% ± 0.57%/10 mL, P = .560). Postoperatively, corrected left ventricular global longitudinal strain worsened in both groups but improved significantly during late follow-up, returning to preoperative values (resect: 1.39% ± 0.49% to 1.71% ± 0.56%/10 mL, P < .001 and respect: 1.30% ± 0.45% to 1.70% ± 0.54%/10 mL, P < .001). Mixed model analysis showed no significant effect on the corrected left ventricular global longitudinal strain when comparing the 2 different surgical repair techniques over time (P = .943).

Conclusions: Our study showed that both leaflet resection and chordal replacement repair techniques are effective at preserving postoperative left ventricular function in patients with posterior mitral valve leaflet prolapse and significant regurgitation.
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http://dx.doi.org/10.1016/j.jtcvs.2021.02.017DOI Listing
February 2021

Sex differences in coronary plaque changes assessed by serial computed tomography angiography.

Int J Cardiovasc Imaging 2021 Mar 10. Epub 2021 Mar 10.

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2 ± 1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (β -1.3 ± 0.4%; p < 0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p < 0.05) whilst women younger than 55 years demonstrated more regression of fibrous (β -0.8 ± 0.3% per year; p = 0.002) and non-calcified PAV (β -0.7 ± 0.3% per year; p = 0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.).
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http://dx.doi.org/10.1007/s10554-021-02204-4DOI Listing
March 2021

Mini-, Micro-, and Conventional Electrodes: An in Vivo Electrophysiology and Ex Vivo Histology Head-to-Head Comparison.

JACC Clin Electrophysiol 2021 02 28;7(2):197-205. Epub 2020 Oct 28.

Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Objectives: This study sought to assess the relative effect of catheter, tissue, and catheter-tissue parameters, on the ability to determine the amount of viable myocardium in vivo.

Background: Although multiple variables impact bipolar voltages (BVs), electrode size, interelectrode spacing, and directional dependency are of particular interest with the development of catheters incorporating mini and microelectrodes.

Methods: Nine swine with early reperfusion myocardial infarctions were mapped using the QDot catheter and then remapped using a Pentaray catheter. All QDot points were matched with Pentaray points within 5 mm. The swine were sacrificed, and mapping data projected onto the heart. Transmural biopsies corresponding to mapping points were obtained, allowing a comparison of electrograms recorded by mini, micro-, and conventional electrodes with histology.

Results: The conventional BV of 2,322 QDot points was 1.9 ± 1.3 mV. The largest of the 3 microelectrode BVs (BV) average 4.8 ± 3.1 mV. The difference between the largest (BV) and smallest (BV) at a given location was 53.7 ± 18.1%. The relationships between both BV and BV and between the conventional BV and BV were positively related but with a significant spread in data, which was more pronounced for the latter. Pentaray points positively related to the BV with poor fit. On histology, increasing viable myocardium increased voltage, but both the slope coefficient and fit were best for BV.

Conclusions: Using histology, we could demonstrate that BV is superior to identify viable myocardium compared with BV and BV using the Pentaray catheter. The ability to simultaneously record 3 BVs with different orientations, for the same beat, with controllable contact and selecting BV for local BV may partially compensate for wave front direction.
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http://dx.doi.org/10.1016/j.jacep.2020.08.014DOI Listing
February 2021

Biological stratification of clinical disease courses in childhood immune thrombocytopenia.

J Thromb Haemost 2021 Apr 18;19(4):1071-1081. Epub 2021 Mar 18.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes.

Objective: To predict the response to intravenous immunoglobulins (IVIg) and ITP disease course using genetic and immune markers.

Methods: Children aged younger than 7 years with newly diagnosed ITP (N = 147) from the Treatment With or Without IVIG for Kids with ITP study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies.

Results: In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 × 10 /L) that lasted for at least 1 month (complete sustained response [CSR]) and 32 exhibited no or a temporary response (absence of a sustained response [ASR]). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: (1) hemoglobin; (2) platelet count; (3) genetic polymorphisms of Fc-receptor (FcγR) IIc; (4) the presence of immunoglobulin G (IgG) anti-platelet antibodies; and (5) preceding vaccination. The ASR sensitivity was 0.91 (95% confidence interval, 0.80-1.00) and specificity was 0.67 (95% confidence interval, 0.53-0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during 1 year of follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses.

Conclusions: The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
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http://dx.doi.org/10.1111/jth.15232DOI Listing
April 2021

A clinical prediction score for transient versus persistent childhood immune thrombocytopenia.

J Thromb Haemost 2021 01 27;19(1):121-130. Epub 2020 Nov 27.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Essentials There is a need for improved tools to predict persistent and chronic immune thrombocytopenia (ITP). We developed and validated a clinical prediction model for recovery from newly diagnosed ITP. The Childhood ITP Recovery Score predicts transient vs. persistent ITP and response to intravenous immunoglobulins. The score may serve as a useful tool for clinicians to individualize patient care. ABSTRACT: Background Childhood immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The prognosis (transient, persistent, or chronic ITP) remains difficult to predict. The morbidity is most pronounced in children with persistent and chronic ITP. Clinical characteristics are associated with ITP outcomes, but there are no validated multivariate prediction models. Objective Development and external validatation of the Childhood ITP Recovery Score to predict transient versus persistent ITP in children with newly diagnosed ITP. Methods Patients with a diagnosis platelet count ≤ 20 × 10 /L and age below 16 years were included from two prospective multicenter studies (NOPHO ITP study, N = 377 [development cohort]; TIKI trial, N = 194 [external validation]). The primary outcome was transient ITP (complete recovery with platelets ≥100 × 10 /L 3 months after diagnosis) versus persistent ITP. Age, sex, mucosal bleeding, preceding infection/vaccination, insidious onset, and diagnosis platelet count were used as predictors. Results In external validation, the score predicted transient versus persistent ITP at 3 months follow-up with an area under the receiver operating characteristic curve of 0.71. In patients predicted to have a high chance of recovery, we observed 85%, 90%, and 95% recovered 3, 6, and 12 months after the diagnosis. For patients predicted to have a low chance of recovery, this was 32%, 46%, and 71%. The score also predicted cessation of bleeding symptoms and the response to intravenous immunoglobulins (IVIg). Conclusion The Childhood ITP Recovery Score predicts prognosis and may be useful to individualize clinical management. In future research, the additional predictive value of biomarkers can be compared to this score. A risk calculator is available (http://www.itprecoveryscore.org).
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http://dx.doi.org/10.1111/jth.15125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839442PMC
January 2021

Regurgitant Volume/Left Ventricular End-Diastolic Volume Ratio: Prognostic Value in Patients With Secondary Mitral Regurgitation.

JACC Cardiovasc Imaging 2021 Apr 19;14(4):730-739. Epub 2020 Aug 19.

Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Objectives: The purpose of this study was to investigate the prognostic implications of the ratio of mitral regurgitant volume (RVol) to left ventricular (LV) end-diastolic volume (EDV) in patients with significant secondary mitral regurgitation (MR).

Background: Quantification of secondary MR remains challenging, and its severity can be over- or underestimated when using the proximal isovelocity surface area method, which does not take LV volume into account. This limitation can be addressed by normalizing mitral RVol to LVEDV.

Methods: A total of 379 patients (mean age 67 ± 11 years; 63% male) with significant (moderate and severe) secondary MR were divided into 2 groups according to the RVol/EDV ratio: RVol/EDV ≥20% (greater MR/smaller EDV) and <20% (smaller MR/larger EDV). The primary endpoint was all-cause mortality.

Results: During median (interquartile range) follow-up of 50 (26 to 94) months, 199 (52.5%) patients died. When considering patients receiving medical therapy only, patients with RVol/EDV ratio ≥20% tended to have higher mortality rates than those with RVol/EDV ratio <20% (5-year estimated rates 24.1% vs. 18.4%, respectively; p = 0.077). Conversely, when considering the entire follow-up period including mitral valve interventions, patients with a higher RVol/EDV ratio (≥20%) had lower rates of all-cause mortality compared with patients with RVol/EDV ratio <20% (5-year estimated rates 39.0% vs. 44.8%, respectively; p = 0.018). On multivariable analysis, higher RVol/EDV ratio (per 5% increment as a continuous variable) was independently associated with lower all-cause mortality (0.93; p = 0.023).

Conclusions: In patients with significant secondary MR treated medically, survival tended to be lower in those with a higher RVol/EDV ratio. Conversely, a higher RVol/EDV ratio was independently associated with reduced all-cause mortality. when mitral valve interventions were taken into consideration.
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http://dx.doi.org/10.1016/j.jcmg.2020.06.032DOI Listing
April 2021

Association between reduced heart rate variability components and supraventricular tachyarrhythmias in patients with a systemic right ventricle.

Auton Neurosci 2020 09 26;227:102696. Epub 2020 Jun 26.

Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: Patients with a systemic right ventricle are prone to develop heart failure. Abnormal heart rate variability (HRV), a measure of autonomic dysfunction, is associated with morbidity and mortality in patients with left ventricular failure. The association between HRV and supraventricular arrhythmias (SVTs), which are associated with adverse events in this population, was assessed.

Methods: 24-Hour Holter recordings of patients with a systemic right ventricle and healthy controls were analysed in a retrospective cohort study. HRV was calculated and compared between groups. Correlation coefficients were determined for HRV variables and clinical characteristics. The relation between HRV and SVTs was investigated with linear regression.

Results: The patient group included 29 patients (69%) late after Mustard or Senning correction for transposition of the great arteries, and 13 patients with congenitally corrected transposition of the great arteries (31%). The control group included 38 subjects. HRV was significantly lower in patients compared with controls. In the patient group, lower SDANN (standard deviation of the average NN intervals calculated over 5-minute intervals) was independently associated with a higher number of supraventricular arrhythmias (95% CI -0.03 to -0.0004, p = 0.045). In exploratory correlation analysis, several HRV variables correlated with echocardiographic systemic right ventricular function (rho = 0.36, p = 0.02 for SDANN), and exercise capacity (rho = 0.39, p = 0.05 for SDANN).

Conclusion: In patients with a systemic right ventricle, HRV is lower compared with controls and (SDANN) is independently associated with supraventricular arrhythmias.
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http://dx.doi.org/10.1016/j.autneu.2020.102696DOI Listing
September 2020

Correlates and Long-Term Implications of Left Ventricular Mechanical Dispersion by Two-Dimensional Speckle-Tracking Echocardiography in Patients with ST-Segment Elevation Myocardial Infarction.

J Am Soc Echocardiogr 2020 08 4;33(8):964-972. Epub 2020 May 4.

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

Background: Left ventricular (LV) mechanical dispersion (LVMD), measured with speckle-tracking echocardiography (STE) after ST-segment elevation myocardial infarction (STEMI), has been proposed as a measurement of regional heterogeneity of myocardial contraction and may reflect changes in the myocardial structure (e.g., fibrosis or edema). Further insight into this parameter may aid in the risk stratification of STEMI patients.

Methods: A total of 1,000 STEMI patients (77% male, 60 ± 12 years) treated with primary percutaneous coronary intervention were retrospectively analyzed. The LVMD was assessed with two-dimensional STE within 48 hours following the index infarction. Patients were followed for the occurrence of all-cause mortality.

Results: After a median follow-up of 117 months, 229 (23%) patients died. Nonsurvivors showed worse LV ejection fraction (43% ± 10% vs 48% ± 9%; P < .001) and global longitudinal strain (-12.0% ± 3.5% vs -14.2% ± 3.5%; P = .001) and prolonged LVMD (63 [interquartile range, 50-85] msec vs 52 [interquartile range, 42-63] msec; P < .001) compared with survivors. Increasing age, systolic blood pressure, and heart rate at discharge as well as diabetes mellitus, anterior STEMI, TIMI flow < 2, less usage of angiotensin converter enzyme inhibitors or angiotensin receptor blockers, and impaired LV global longitudinal strain were independently associated with more prolonged LVMD. On multivariable analysis, prolonged LVMD was independently associated with increased risk of all-cause mortality (hazard ratio = 1.012; 95% CI, 1.005-1.018; P = .001) and had incremental value for all-cause mortality over clinical and echocardiographic parameters.

Conclusions: In contemporary STEMI patients, prolonged LVMD was associated with various clinical and echocardiographic parameters. Prolonged LVMD was associated with worse long-term outcome.
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http://dx.doi.org/10.1016/j.echo.2020.03.010DOI Listing
August 2020

Impact of Clinical Characteristics and Statins on Coronary Plaque Progression by Serial Computed Tomography Angiography.

Circ Cardiovasc Imaging 2020 03 12;13(3):e009750. Epub 2020 Mar 12.

Department of Cardiology, Leiden University Medical Center, The Netherlands (J.M.S., A.R.v.R., M.E.M., A.J.S.).

Background Progression of coronary artery disease using serial coronary computed tomography angiography (CTA) is of clinical interest. Our primary aim was to prospectively assess the impact of clinical characteristics and statin use on quantitatively assessed coronary plaque progression in a low-risk study population during long-term follow-up. Methods Patients who previously underwent coronary CTA for suspected coronary artery disease were prospectively included to undergo follow-up coronary CTA. The primary end point was coronary artery disease progression, defined as the absolute annual increase in total, calcified, and noncalcified plaque volume by quantitative CTA analysis. Results In total, 202 patients underwent serial coronary CTA with a mean interscan period of 6.2±1.4 years. On a per-plaque basis, increasing age (β=0.070; =0.058) and hypertension (β=1.380; =0.075) were nonsignificantly associated with annual total plaque progression. Male sex (β=1.676; =0.009), diabetes mellitus (β=1.725; =0.012), and statin use (β=1.498; =0.046) showed an independent association with annual progression of calcified plaque. While hypertension (β=2.259; =0.015) was an independent determinant of noncalcified plaque progression, statin use (β=-2.178; =0.050) was borderline significantly associated with a reduced progression of noncalcified plaque. Conclusions Statin use was associated with an increased progression of calcified coronary plaque and a reduced progression of noncalcified coronary plaque, potentially reflecting calcification of the noncalcified plaque component. Whereas hypertension was the only modifiable risk factor predictive of noncalcified plaque progression, diabetes mellitus mainly led to an increase in calcified plaque. These findings could yield the need for intensified preventive treatment of patients with diabetes mellitus and hypertension to slow and stabilize coronary artery disease progression and improve clinical outcome.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.009750DOI Listing
March 2020

Coronary anomalies in tetralogy of Fallot - A meta-analysis.

Int J Cardiol 2020 05 17;306:78-85. Epub 2020 Feb 17.

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands.

Background: An anomalous coronary artery is reported in 2% to 23% of patients with tetralogy of Fallot (TOF). Knowledge of coronary anatomy prior to corrective surgery is vital to avoid damage to vessels crossing the right ventricular outflow tract (RVOT). A meta-analysis on the prevalence of anomalous coronary arteries in TOF is lacking to date. Here, an overview of coronary anomalies in TOF is provided and implications for patient management are discussed.

Methods: PubMed, Embase and Web of Science were searched. Analysis was done using Revman 5.3 (Cochrane Community, London). The primary analysis focused on the origin and proximal course of the right and left coronary arteries. In addition, the prevalence of large conus arteries and coronary arteriovenous fistulas (CAVF) was calculated.

Results: Twenty-eight studies, encompassing 6956 patients, were included; 6% of TOF patients have an anomalous coronary artery. Hereof, 72% cross the RVOT; the majority of the remaining 28% courses behind the aorta. Six percent of patients have a large conus artery and 4% a CAVF. Other coronary anomalies include a left or right coronary artery from the pulmonary trunk or left or right pulmonary artery, coronary tree hypoplasia and anastomoses between coronary and bronchial arteries.

Conclusions: The prevalence of coronary anomalies in TOF is 4-6%. In patients with an anomalous coronary artery, 72% cross the RVOT. The combined risk of encountering an anomalous coronary artery or a large conus artery crossing the RVOT is 10.3%. Coronary anatomy should be defined before surgery and the surgical approach adapted accordingly.
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http://dx.doi.org/10.1016/j.ijcard.2020.02.037DOI Listing
May 2020

The Effect of Ultraviolet B Irradiation Compared with Oral Vitamin D Supplementation on the Well-being of Nursing Home Residents with Dementia: A Randomized Controlled Trial.

Int J Environ Res Public Health 2020 03 5;17(5). Epub 2020 Mar 5.

Department of Public Health and Primary Care, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

There are indications that ultraviolet B (UVB) exposure has beneficial effects on well-being through mechanisms other than vitamin D synthesis alone. We conducted a randomized controlled multicenter trial to compare the effects of UVB light and vitamin D supplementation (VD) in terms of the well-being of nursing home residents with dementia. Participants were randomly assigned to the intervention group (UVB group, = 41; half-body UVB irradiation, twice weekly over 6 months, with 1 standard erythema dose (SED)) or to the control group (VD group, = 37; 5600 International units (IU) cholecalciferol supplementation once a week). The main outcome was well-being, measured by the Cohen-Mansfield Agitation Inventory (CMAI) and the Cornell scale for depression in dementia at 0, 3, and 6 months. Secondary outcomes were QUALIDEM quality of life domains and biochemical parameters of bone homeostasis. Intention-to-treat analysis with linear mixed modeling showed no significant between-group differences on agitation ( = 0.431) or depressive symptoms ( = 0.982). At six months, the UVB group showed less restless/tense behavior compared to the VD group (mean difference of the mean change scores 2.2, 95% CI 0.8 to 3.6; = 0.003 for group x time interaction) and lower serum 25(OH)D3 concentration (estimated mean difference - 21.9, 95% CI -32.6 to -11.2; = 0.003 for group difference). The exposure of nursing home residents with dementia to UVB light showed no positive benefits in terms of wellbeing. UVB treatment may have a positive effect on the restless/tense behavior characteristic of advanced dementia but more research is needed to confirm this finding.
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http://dx.doi.org/10.3390/ijerph17051684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084916PMC
March 2020

Prognostic Value of Left Ventricular Global Longitudinal Strain in Patients With Secondary Mitral Regurgitation.

J Am Coll Cardiol 2020 02;75(7):750-758

Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: Left ventricular (LV) systolic function may be overestimated in patients with secondary mitral regurgitation (MR) when using LV ejection fraction (EF). LV global longitudinal strain (GLS) is a less load-dependent measure of LV function. However, the prognostic value of LV GLS in secondary MR has not been evaluated.

Objectives: This study sought to demonstrate the prognostic value of LV GLS over LVEF in patients with secondary MR.

Methods: A total of 650 patients (mean 66 ± 11 years of age, 68% men) with significant secondary MR were included. The study population was subdivided based on the LV GLS value at which the hazard ratio (HR) for all-cause mortality was >1 using a spline curve analysis (LV GLS <7.0%, impaired LV systolic function vs. LV GLS ≥7.0%, preserved LV systolic function). The primary endpoint was all-cause mortality.

Results: During a median follow-up of 56 (interquartile range: 28 to 106 months) months, 334 (51%) patients died. Patients with a more impaired LV GLS showed significantly higher mortality rates at 1-, 2-, and 5-year follow-up (13%, 23%, and 44%, respectively) when compared with patients with more preserved LV systolic function (5%, 14%, and 31%, respectively). On multivariable analysis, LV GLS <7.0% was associated with increased mortality (HR: 1.337; 95% confidence interval: 1.038 to 1.722; p = 0.024), whereas LVEF ≤30% was not (HR: 1.055; 95% confidence interval: 0.794 to 1.403; p = 0.711).

Conclusions: In patients with secondary MR, impaired LV GLS was independently associated with an increased risk for all-cause mortality, whereas LVEF was not. LV GLS may therefore be useful in the risk stratification of patients with secondary MR.
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http://dx.doi.org/10.1016/j.jacc.2019.12.024DOI Listing
February 2020

Construction and assessment of prediction rules for binary outcome in the presence of missing predictor data using multiple imputation and cross-validation: Methodological approach and data-based evaluation.

Biom J 2020 05 13;62(3):724-741. Epub 2020 Feb 13.

Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

We investigate calibration and assessment of predictive rules when missing values are present in the predictors. Our paper has two key objectives. The first is to investigate how the calibration of the prediction rule can be combined with use of multiple imputation to account for missing predictor observations. The second objective is to propose such methods that can be implemented with current multiple imputation software, while allowing for unbiased predictive assessment through validation on new observations for which outcome is not yet available. We commence with a review of the methodological foundations of multiple imputation as a model estimation approach as opposed to a purely algorithmic description. We specifically contrast application of multiple imputation for parameter (effect) estimation with predictive calibration. Based on this review, two approaches are formulated, of which the second utilizes application of the classical Rubin's rules for parameter estimation, while the first approach averages probabilities from models fitted on single imputations to directly approximate the predictive density for future observations. We present implementations using current software that allow for validation and estimation of performance measures by cross-validation, as well as imputation of missing data in predictors on the future data where outcome is missing by definition. To simplify, we restrict discussion to binary outcome and logistic regression throughout. Method performance is verified through application on two real data sets. Accuracy (Brier score) and variance of predicted probabilities are investigated. Results show substantial reductions in variation of calibrated probabilities when using the first approach.
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http://dx.doi.org/10.1002/bimj.201800289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217034PMC
May 2020

Clamping versus nonclamping thoracoscopic box ablation in long-standing persistent atrial fibrillation.

J Thorac Cardiovasc Surg 2020 Aug 28;160(2):399-405. Epub 2019 Aug 28.

Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Objective: To compare clinical outcomes of clamping devices and linear nonclamping devices for isolation of the posterior left atrium (box) in thoracoscopic ablation of long-standing persistent atrial fibrillation.

Methods: Eighty patients who underwent thoracoscopic pulmonary vein and box isolation using a bipolar clamping device (42 patients) or bipolar nonclamping device (38 patients) to create the roof/inferior lesions for box isolation were included from 2 centers. Follow-up consisted of 24-hour Holter at regular intervals. Freedom from AF during 1-year follow-up and catheter repeat interventions were compared between groups.

Results: Acute intraoperative electrical isolation of the box compartment was significantly higher in the clamping group than in the nonclamping group (100% and 79%, respectively, P < .01). At 1-year follow-up, 91% of the clamping group and 79% of the nonclamping group were in sinus rhythm. During 1-year follow-up, recurrence rates did not significantly differ between the 2 groups (P = .08). Repeat catheter interventions were required in 10% of the clamping group and 21% of the nonclamping group (P = .15). Conduction gaps in the roof or inferior lesions were found in 1 patient (2%) in the clamping group versus 4 patients (11%) in the nonclamping group (P = .13).

Conclusions: Thoracoscopic pulmonary vein and box isolation are highly effective in restoring sinus rhythm in long-standing persistent atrial fibrillation on short-term follow-up. Comparison of clamping and nonclamping devices revealed lower rates of intraoperative exit block of the box in the nonclamping group. However, this did not translate into a significant difference in atrial fibrillation freedom at short-term (1-year) follow-up.
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http://dx.doi.org/10.1016/j.jtcvs.2019.07.104DOI Listing
August 2020

Risk factors and clinical significance of elevated mitral valve gradient following valve repair for degenerative disease.

Eur J Cardiothorac Surg 2020 02;57(2):293-299

Department of Cardiothoracic Surgery, Leiden University Medical Centre, Leiden, Netherlands.

Objectives: The risk factors and clinical effect of elevated mitral valve (MV) gradients after valve repair for degenerative valve disease remain insufficiently understood.

Methods: Between January 2004 and December 2015, a total of 484 patients underwent valve repair for degenerative disease. A true-sized full annuloplasty ring was implanted in all cases. We analysed the effect of preoperative and intraoperative factors on the postrepair gradient. Additionally, we explored the effect of postrepair gradients on long-term outcomes.

Results: On linear regression analysis, postrepair MV gradients were associated with patient age (coefficient = -0.110, standard error = 0.005, P = 0.034), body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008), implanted annuloplasty ring size (coefficient = -0.181, standard error = 0.018, P < 0.001) and the use of Physio I ring (coefficient = 0.414, standard error = 0.122, P = 0.001). On multivariable analysis, postrepair MV gradient was not associated with overall survival [hazard ratio (HR) 1.034, 95% confidence interval (CI) 0.889-1.203; P = 0.66] or freedom from atrial fibrillation (HR 0.849, 95% CI 0.682-1.057; P = 0.14), but did emerge as a risk factor for MV reintervention (HR 1.378, 95% CI 1.033-1.838; P = 0.029). Two out of 11 reinterventions were performed due to MV stenosis and in both patients, high postrepair gradients were seen readily on predischarge echocardiography.

Conclusions: Following valve repair for degenerative MV disease, elevated gradients occur even when true-sized annuloplasty is performed. The late clinical results of valve repair with elevated postrepair gradient are impaired and further studies are needed to explore preventive measures aimed at resolving the issue.
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http://dx.doi.org/10.1093/ejcts/ezz178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964229PMC
February 2020

Prognostic Implications of Right Ventricular Remodeling and Function in Patients With Significant Secondary Tricuspid Regurgitation.

Circulation 2019 09 12;140(10):836-845. Epub 2019 Jun 12.

Department of Cardiology (M.F.D., E.A.P., P.v.d.B., L.G., E.G., O.S.v.G., N.A.M., V.D., J.J.B.), Leiden University Medical Center, The Netherlands.

Background: In patients with significant (moderate and severe) tricuspid regurgitation (TR), the decision to intervene is influenced by right ventricular (RV) size and function. RV remodeling in significant secondary TR has been underexplored. The aim of this study was to characterize RV remodeling in patients with significant secondary TR and to investigate its prognostic implications.

Methods: RV remodeling was characterized by transthoracic echocardiography in 1292 patients with significant secondary TR (median age 71 [62-78]; 50% male). Four patterns of RV remodeling were defined according to the presence of RV dilation (tricuspid annulus≥40 mm) and RV systolic dysfunction (tricuspid annulus systolic excursion plane<17 mm): pattern 1, normal RV size and systolic function; pattern 2, dilated RV with preserved systolic function; pattern 3, normal RV size with systolic dysfunction; and pattern 4, dilated RV systolic dysfunction. The primary end point was all-cause mortality and the event rates were compared across the 4 patterns of RV remodeling.

Results: A total of 183 (14%) patients showed pattern 1 RV remodeling; 256 (20%) showed pattern 2; 304 (24%) presented with pattern 3; and 549 (43%) had pattern 4 RV remodeling. Patients with pattern 4 RV remodeling were more frequently male; more often had coronary artery disease, worse renal function, and impaired left ventricular ejection fraction; and were more often symptomatic. Only 98 (8%) patients underwent tricuspid valve annuloplasty during follow-up. During a median follow-up of 34 (interquartile range, 0-60) months, 510 (40%) patients died. The 5-year survival rate was significantly worse in patients presenting with patterns 3 and 4 RV remodeling in comparison with pattern 1 (52% and 49% versus 70%; P=0.002 and P<0.001, respectively), and were independently associated with poor outcome on multivariable analysis.

Conclusions: In patients with significant secondary TR, patients with RV systolic dysfunction have worse clinical outcome regardless of the presence of RV dilation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039630DOI Listing
September 2019

Prognostic implications of global, left ventricular myocardial work efficiency before cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2019 Dec;20(12):1388-1394

Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.

Aims: Cardiac resynchronization therapy (CRT) restores mechanical efficiency to the failing left ventricular (LV) by resynchronization of contraction. Global, LV myocardial work efficiency (GLVMWE) can be quantified non-invasively with echocardiography. The prognostic implication of GLVMWE remains unexplored, and we therefore related GLVMWE before CRT to long-term prognosis.

Methods And Results: Data were analysed from an ongoing registry of patients with Class I indications for CRT. GLVMWE was defined as the ratio of constructive work in all LV segments, divided by the sum of constructive and wasted work in all LV segments, as a percentage. It was derived from speckle tracking strain echocardiography and non-invasive blood pressure measurements, taken pre-CRT. Patients were dichotomized according to baseline, median GLVMWE [75%; interquartile range (IQR) 66-81%]. A total of 153 patients (66 ± 10 years, 72% male, 48% ischaemic heart disease) were analysed. After a median follow-up of 57 months (IQR 28-76 months), 31% of patients died. CRT recipients with less efficient baseline energetics (GLVMWE <75%) demonstrated lower event rates than patients with more efficient baseline energetics (GLVMWE ≥75%) (log-rank test, P = 0.029). On multivariable analysis, global LV wasted work ratio <75% pre-CRT was independently associated with a decreased risk of all-cause mortality (hazard ratio 0.48, 95% confidence interval 0.25-0.92; P = 0.027), suggesting that the potential for improvement in LV efficiency is important for CRT benefit.

Conclusion: GLVMWE can be derived non-invasively from speckle tracking strain echocardiography and non-invasive blood pressure recordings. A lower GLVMWE before CRT is independently associated with improved long-term outcome.
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http://dx.doi.org/10.1093/ehjci/jez095DOI Listing
December 2019

Time course of left ventricular remodelling and mechanics after aortic valve surgery: aortic stenosis vs. aortic regurgitation.

Eur Heart J Cardiovasc Imaging 2019 Oct;20(10):1105-1111

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, The Netherlands.

Aims: Pressure overload in aortic stenosis (AS) and both pressure and volume overload in aortic regurgitation (AR) induce concentric and eccentric hypertrophy, respectively. These structural changes influence left ventricular (LV) mechanics, but little is known about the time course of LV remodelling and mechanics after aortic valve surgery (AVR) and its differences in AS vs. AR. The present study aimed to characterize the time course of LV mass index (LVMI) and LV mechanics [by LV global longitudinal strain (LV GLS)] after AVR in AS vs. AR.

Methods And Results: Two hundred and eleven (61 ± 14 years, 61% male) patients with severe AS (63%) or AR (37%) undergoing surgical AVR with routine echocardiographic follow-up at 1, 2, and/or 5 years were evaluated. Before AVR, LVMI was larger in AR patients compared with AS. Both groups showed moderately impaired LV GLS, but preserved LV ejection fraction. After surgery, both groups showed LV mass regression, although a more pronounced decline was seen in AR patients. Improvement in LV GLS was observed in both groups, but characterized by an initial decline in AR patients while LV GLS in AS patients remained initially stable.

Conclusion: In severe AS and AR patients undergoing AVR, LV mass regression and changes in LV GLS are similar despite different LV remodelling before AVR. In AR, relief of volume overload led to reduction in LVMI and an initial decline in LV GLS. In contrast, relief of pressure overload in AS was characterized by a stable LV GLS and more sustained LV mass regression.
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http://dx.doi.org/10.1093/ehjci/jez049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753383PMC
October 2019

Growth Differentiation Factor-15 Levels at Admission Provide Incremental Prognostic Information on All-Cause Long-term Mortality in ST-Segment Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention.

Cardiol Ther 2019 Jun 30;8(1):29-41. Epub 2019 Jan 30.

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: To investigate the additive prognostic value of growth differentiation factor (GDF-15) levels in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneously coronary intervention (pPCI) with 10-year mortality on top of clinical characteristics and known cardiac biomarkers.

Methods: Baseline serum GDF-15 levels were measured in 290 STEMI patients treated with pPCI in the MISSION! intervention trial conducted from February 1, 2004 through October 31, 2006. The incremental prognostic value of GDF-15 and NTproBNP levels was evaluated on top of clinical characteristics using Cox proportional hazards analysis, Chi-square models and C-index. Outcome was 10-year all-cause mortality.

Results: Mean age was 59.0 ± 11.5 years and 65 (22.4) patients were female. A total of 37 patients died during a follow-up of 9.4 (IQR 8.8-10.0) years. Multivariable Cox regression revealed GDF-15 and NTproBNP levels above median to be independently associated with 10-year all-cause mortality [HR GDF-15, 2.453 (95% CI 1.064-5.658), P = 0.04; HR NTproBNP, 2.413 (95% CI 1.043-5.564), P = 0.04] after correction for other clinical variables. Stratified by median GDF-15 (37.78 pmol/L) and NTproBNP (11.74 pmol/L) levels, Kaplan-Meier curves showed significant better survival for patients with GDF-15 and NTproBNP levels below the median versus above the median. The likelihood ratio test showed a significant incremental value of GDF-15 (P = 0.03) as compared with a model with clinically important variables and NTproBNP. The C-statistics for this model improved from 0.82 to 0.84 when adding GDF-15.

Conclusion: GDF-15 levels at admission in STEMI patients are independently associated with 10-year all-cause mortality rates and could improve risk stratification on top of clinical variables and other cardiac biomarkers.
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http://dx.doi.org/10.1007/s40119-019-0127-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525222PMC
June 2019

Referral of patients for fractional flow reserve using quantitative flow ratio.

Eur Heart J Cardiovasc Imaging 2019 Nov;20(11):1231-1238

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, The Netherlands.

Aims: Quantitative flow ratio (QFR) is a recently developed technique to calculate fractional flow reserve (FFR) based on 3D quantitative coronary angiography and computational fluid dynamics, obviating the need for a pressure-wire and hyperaemia induction. QFR might be used to guide patient selection for FFR and subsequent percutaneous coronary intervention (PCI) referral in hospitals not capable to perform FFR and PCI. We aimed to investigate the feasibility to use QFR to appropriately select patients for FFR referral.

Methods And Results: Patients who underwent invasive coronary angiography in a hospital where FFR and PCI could not be performed and were referred to our hospital for invasive FFR measurement, were included. Angiogram images from the referring hospitals were retrospectively collected for QFR analysis. Based on QFR cut-off values of 0.77 and 0.86, our patient cohort was reclassified to 'no referral' (QFR ≥0.86), referral for 'FFR' (QFR 0.78-0.85), or 'direct PCI' (QFR ≤0.77). In total, 290 patients were included. Overall accuracy of QFR to detect an invasive FFR of ≤0.80 was 86%. Based on a QFR cut-off value of 0.86, a 50% reduction in patient referral for FFR could be obtained, while only 5% of these patients had an invasive FFR of ≤0.80 (thus, these patients were incorrectly reclassified to the 'no referral' group). Furthermore, 22% of the patients that still need to be referred could undergo direct PCI, based on a QFR cut-off value of 0.77.

Conclusion: QFR is feasible to use for the selection of patients for FFR referral.
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http://dx.doi.org/10.1093/ehjci/jey187DOI Listing
November 2019

Impact of hepatic encephalopathy on liver transplant waiting list mortality in regions with different transplantation rates.

Clin Transplant 2018 11 8;32(11):e13412. Epub 2018 Oct 8.

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Overt hepatic encephalopathy (OHE) negatively impacts the prognosis of liver transplant candidates. However, it is not taken into account in most prioritizing organ allocation systems. We aimed to assess the impact of OHE on waitlist mortality in 3 cohorts of cirrhotic patients awaiting liver transplantation, with differences in the composition of patient population, transplantation policy, and transplantation rates. These cohorts were derived from two centers in the Netherlands (reference and validation cohort, n = 246 and n = 205, respectively) and one in Spain (validation cohort, n = 253). Competing-risk regression analysis was applied to assess the association of OHE with 1-year waitlist mortality. OHE was found to be associated with mortality, independently of MELD score, other cirrhosis-related complications and hepatocellular carcinoma (HCC; sHR = 4.19, 95% CI = 1.9-9.5, P = 0.001). The addition of extra MELD points for OHE counteracted its negative impact on survival. These findings were confirmed in the Dutch validation cohort, whereas in the Spanish cohort, containing a significantly greater proportion of HCC and with higher transplantation rates, OHE was not associated with mortality. In conclusion, OHE is an independent risk factor for 1-year waitlist mortality and might be a prioritization rule for organ allocation. However, its impact seems to be attenuated in settings with significantly higher transplantation rates.
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http://dx.doi.org/10.1111/ctr.13412DOI Listing
November 2018

To what extent do autoantibodies help to identify high-risk patients in systemic sclerosis?

Clin Exp Rheumatol 2018 Jul-Aug;36 Suppl 113(4):109-117. Epub 2018 Jul 18.

Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.

Objectives: To evaluate the additive value of autoantibodies in identifying systemic sclerosis (SSc) patients with high complication risk.

Methods: Patients entering the Combined Care In SSc cohort, Leiden University Medical Centre between April 2009 and May 2016 were included. Subgroups of patients were determined using hierarchical clustering, performed on Principal Component Analysis scores, 1) using baseline data of demographic and clinical variables only and 2) with additional use of antibody status. Disease-risk within subgroups was assessed by evaluating 5-year mortality rates. Clinical and autoantibody characteristics of obtained subgroups were compared.

Results: In total 407 SSc patients were included, of which 91% (n=371) fulfilled ACR/EULAR 2013 criteria for SSc. Prevalences of autoantibodies were: anti-centromere 37%, anti-topoisomerase (ATA) 24%, anti-RNA polymerase III 5%, anti-fibrillarin 4% and anti-Pm/Scl 5%. Clinical cluster analysis identified 4 subgroups, with two subgroups showing higher than average mortality (resp. 17% and 7% vs. total group mortality of 4%). ATA-positivity ranged from 10 to 21% in low-risk groups and from 30 to 49% among high-risk groups. Adding autoantibody status to the cluster process resulted in 5 subgroups with 3 showing higher than average mortality. Still, 22% of ATA- positive patients were clustered into a low-risk subgroup, while the total number of patients stratified to a high-risk subgroup increased.

Conclusions: Autoantibodies only partially contribute to risk-stratification and clinical subsetting in SSc. The current findings confirm that not all ATA-positive patients have worse prognosis and as such, additional biomarkers are needed to guide clinical follow-up in SSc.
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January 2019

Association of Left Ventricular Global Longitudinal Strain With Asymptomatic Severe Aortic Stenosis: Natural Course and Prognostic Value.

JAMA Cardiol 2018 09;3(9):839-847

Heart Lung Center, Leiden University Medical Center, Leiden, the Netherlands.

Importance: The optimal timing to operate in patients with asymptomatic severe aortic stenosis (AS) remains controversial. Left ventricular global longitudinal strain (LV GLS) may help to identify patients who might benefit from undergoing earlier aortic valve replacement.

Objective: To investigate the prevalence of impaired LV GLS, the natural course of LV GLS, and its prognostic implications in patients with asymptomatic severe AS with preserved left ventricular ejection fraction (LVEF).

Design, Setting, And Participants: This registry-based study included the institutional registries of 3 large tertiary referral centers and 220 patients with asymptomatic severe AS and preserved LVEF (>50%) who were matched for age and sex with 220 controls without structural heart disease. The echocardiograms of patients and controls were performed between 1998 and 2017.

Exposures: Both clinical and echocardiographic data were assessed retrospectively. Severe AS was defined by an indexed aortic valve area less than 0.6 cm2/m2. Left ventricular global longitudinal strain was evaluated on transthoracic echocardiography using speckle tracking imaging.

Main Outcomes And Measures: The prevalence of impaired LV GLS, the natural course of LV GLS, and the association of impaired LV GLS with symptom onset and the need for aortic valve intervention.

Results: Two hundred twenty patients (mean [SD] age, 68 [13] years; 126 men [57%]) were included. Despite comparable LVEF, LV GLS was significantly impaired in patients with asymptomatic severe AS compared with age- and sex-matched controls without AS (mean [SD] LV GLS, -17.9% [2.5%] vs -19.6% [2.1%]; P < .001). After a median follow-up of 12 (interquartile range, 7-23) months, mean (SD) LV GLS significantly deteriorated (-18.0% [2.6%] to -16.3% [2.8%]; P < .001) while LVEF remained unchanged. Patients with impaired LV GLS at baseline (>-18.2%) showed a higher risk for developing symptoms (P = .02) and needing aortic valve intervention (P = .03) at follow-up compared with patients with more preserved LV GLS (≤-18.2%).

Conclusions And Relevance: Subclinical myocardial dysfunction that is characterized by impaired LV GLS is often present in patients with asymptomatic severe AS with preserved LVEF. Left ventricular global longitudinal strain further deteriorates over time and impaired LV GLS at baseline is associated with an increased risk for progression to the symptomatic stage and the need for aortic valve intervention.
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http://dx.doi.org/10.1001/jamacardio.2018.2288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233650PMC
September 2018

Bayesian variable selection logistic regression with paired proteomic measurements.

Biom J 2018 09 25;60(5):1003-1020. Epub 2018 Jun 25.

Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300, RC, Leiden, The Netherlands.

We explore the problem of variable selection in a case-control setting with mass spectrometry proteomic data consisting of paired measurements. Each pair corresponds to a distinct isotope cluster and each component within pair represents a summary of isotopic expression based on either the intensity or the shape of the cluster. Our objective is to identify a collection of isotope clusters associated with the disease outcome and at the same time assess the predictive added-value of shape beyond intensity while maintaining predictive performance. We propose a Bayesian model that exploits the paired structure of our data and utilizes prior information on the relative predictive power of each source by introducing multiple layers of selection. This allows us to make simultaneous inference on which are the most informative pairs and for which-and to what extent-shape has a complementary value in separating the two groups. We evaluate the Bayesian model on pancreatic cancer data. Results from the fitted model show that most predictive potential is achieved with a subset of just six (out of 1289) pairs while the contribution of the intensity components is much higher than the shape components. To demonstrate how the method behaves under a controlled setting we consider a simulation study. Results from this study indicate that the proposed approach can successfully select the truly predictive pairs and accurately estimate the effects of both components although, in some cases, the model tends to overestimate the inclusion probability of the second component.
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http://dx.doi.org/10.1002/bimj.201700182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175404PMC
September 2018

Reduced left ventricular mechanical dispersion at 6 months follow-up after cardiac resynchronization therapy is associated with superior long-term outcome.

Heart Rhythm 2018 11 9;15(11):1683-1689. Epub 2018 May 9.

Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Background: In heart failure (HF) patients, left ventricular mechanical dispersion (LVMD) reflects heterogeneous mechanical activation of the left ventricle. In HF patients, LVMD can be reduced after CRT. Whether lesser LVMD is associated with improved outcome is unknown.

Objective: The purpose of this study was to relate LVMD to long-term prognosis in a large cohort of HF patients after 6 months of cardiac resynchronization therapy (CRT).

Methods: Clinical, echocardiographic, and ventricular arrhythmia (VA) data were analyzed from an ongoing registry of HF recipients of CRT. Baseline (before CRT) and 6-month echocardiograms were evaluated. LVMD was calculated as the standard deviation of the time from onset of the QRS complex to the peak longitudinal strain in a 17-segment model. Patients were divided into 2 groups according to the median LVMD (84 ms) at 6 months post-CRT.

Results: Of 1185 patients (mean age 65 ± 10 years; 76% male), 343 (29%) died during a mean follow-up of 55 ± 36 months. Baseline LVMD was not associated with all-cause mortality and VA at follow-up. In contrast, patients with less LVMD (≤84 ms) at 6 months post-CRT had lower event rates (VA and mortality) compared to those with LVMD >84 ms. On multivariable analysis, greater LVMD at 6 months after CRT was independently associated with an increased risk of mortality (hazard ratio 1.002; P = .037) and VA (hazard ratio 1.003; P = .026).

Conclusion: Larger LVMD at 6 months after CRT is independently associated with all-cause mortality and VA. LVMD may be valuable in identifying patients who remain at high mortality risk after CRT implantation.
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http://dx.doi.org/10.1016/j.hrthm.2018.05.005DOI Listing
November 2018

A Rapid (Differential) Effect of Rosuvastatin and Atorvastatin on High-Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease.

Clin Pharmacol Ther 2018 08 15;104(2):311-316. Epub 2018 May 15.

Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.

Serum troponin within the normal range is an emerging predictor of cardiovascular mortality. We aimed to determine how rapidly high-sensitivity troponin-I (hs-cTnI) levels are lowered by statin therapy in patients with stable cardiovascular disease. In the RADAR substudy, patients were randomized to atorvastatin 20 mg/day (n = 39) or rosuvastatin 10 mg/day (n = 39) and up-titrated at 6-week intervals to 80 mg of atorvastatin or 40 mg of rosuvastatin. Hs-cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow-up. Statin treatment resulted in a mean change of serum hs-cTnI of -8.2% (P = 0.010) after 6 weeks and -12.3% (P = 0.001) after 18 weeks. After 18 weeks, hs-cTnI levels were lowered by 21.8% with atorvastatin and by 4.1% with rosuvastatin (P = 0.001 and P = 0.133, respectively). During statin therapy, serum hs-cTnI levels decreased rapidly within weeks of treatment, suggesting an effect beyond long-term atherosclerosis regression. Mechanisms that mediate this effect require further study.
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http://dx.doi.org/10.1002/cpt.1095DOI Listing
August 2018

Long-term prognostic value of single-photon emission computed tomography myocardial perfusion imaging after primary PCI for STEMI.

Eur Heart J Cardiovasc Imaging 2018 11;19(11):1287-1293

Department of Cardiology, Leiden University Medical Center, Postal Zone 2300 RC, Albinusdreef 2, ZA, Leiden, The Netherlands.

Aims: The aim of this study was to determine the long-term prognostic value of infarct size and myocardial ischaemia on single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).

Methods And Results: In total, 1092 STEMI patients who underwent primary PCI and SPECT MPI within 1-6 months were included (median follow-up time of 6.9 years). In the entire cohort, SPECT infarct size was independently associated with the composite of cardiac death or reinfarction [hazard ratio (HR) per 10% increase in summed rest score 1.33; 95% confidence interval (95% CI) 1.12-1.58; P = 0.001], whereas myocardial ischaemia was not (HR per 5% increase in summed difference score 1.18; 95% CI 0.94-1.48; P = 0.16). Addition of SPECT infarct size to a model including the clinical variables provided significant incremental prognostic value for the prediction of cardiac death or reinfarction (global χ2 13.8 vs. 24.2; P = 0.002), whereas addition of SPECT ischaemia did not add significantly (global χ2 24.2 vs. 25.6; P = 0.24). In the subgroup of patients with left ventricular ejection fraction (LVEF) ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction (HR 1.59; 95% CI 1.15-2.22; P = 0.006), whereas in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction (HR 1.28; 95% CI 1.00-1.63; P = 0.050).

Conclusion: In patients with first STEMI and primary PCI, SPECT infarct size was independently associated with cardiac death and/or reinfarction, whereas myocardial ischaemia was not. In patients with LVEF ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction, whereas myocardial ischaemia was not. Conversely, in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction.
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http://dx.doi.org/10.1093/ehjci/jex332DOI Listing
November 2018

Usefulness of the CRT-SCORE for Shared Decision Making in Cardiac Resynchronization Therapy in Patients With a Left Ventricular Ejection Fraction of ≤35.

Am J Cardiol 2017 Dec 30;120(11):2008-2016. Epub 2017 Aug 30.

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

Individualized estimation of prognosis after cardiac resynchronization therapy (CRT) remains challenging. Our aim was to develop a multiparametric prognostic risk score (CRT-SCORE) that could be used for patient-specific clinical shared decision making about CRT implantation. The CRT-SCORE was derived from an ongoing CRT registry, including 1,053 consecutive patients (age 67 ± 10 years, 76% male). Using preimplantation variables, 100 multiple imputed datasets were generated for model calibration. Based on multivariate Cox regression models, cross-validated linear prognostic scores were calculated, as well as survival fractions at 1 and 5 years. Specifically, the CRT-SCORE was calculated using atrioventricular junction ablation, age, gender, etiology, New York Heart Association class, diabetes, hemoglobin level, renal function, left bundle branch block, QRS duration, atrial fibrillation, left ventricular systolic and diastolic functions, and mitral regurgitation, and showed a good discriminative ability (areas under the curve 0.773 at 1 year and 0.748 at 5 years). During the long-term follow-up (median 60 months, interquartile range 31 to 85), all-cause mortality was observed in 494 (47%) patients. Based on the distribution of the CRT-SCORE, lower- and higher-risk patient groups were identified. Estimated mean survival rates of 98% at 1 year and 92% at 5 years were observed in the lowest 5% risk group (L5 CRT-SCORE: -4.42 to -1.60), whereas the highest 5% risk group (H5 CRT-SCORE: 1.44 to 2.89) showed poor survival rates: 78% at 1 year and 22% at 5 years. In conclusion, the CRT-SCORE allows accurate prediction of 1- and 5-year survival rates after CRT using readily available and CRT-specific clinical, electrocardiographic, and echocardiographic parameters. The model may assist clinicians in counseling patients and in decision making.
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http://dx.doi.org/10.1016/j.amjcard.2017.08.019DOI Listing
December 2017

Inter-ethnic differences in valve morphology, valvular dysfunction, and aortopathy between Asian and European patients with bicuspid aortic valve.

Eur Heart J 2018 04;39(15):1308-1313

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.

Background: Transcatheter aortic valve replacement (TAVR) has been shown safe and feasible in patients with bicuspid aortic valve (BAV) morphology. Evaluation of inter-ethnic differences in valve morphology and function and aortic root dimensions in patients with BAV is important for the worldwide spread of this therapy in this subgroup of patients. Comparisons between large European and Asian cohorts of patients with BAV have not been performed, and potential differences between populations may have important implications for TAVR.

Aim: The present study evaluated the differences in valve morphology and function and aortic root dimensions between two large cohorts of European and Asian patients with BAV.

Methods And Results: Aortic valve morphology was defined on transthoracic echocardiography according to the number of commissures and raphe: type 0 = no raphe and two commissures, type 1 = one raphe and two commissures, type 2 = two raphes and one commissure. Aortic stenosis and regurgitation were graded according to current recommendations. For this study, aortic root dimensions were manually measured on transthoracic echocardiograms at the level of the aortic annulus, sinus of Valsalva (SOV), sinotubular junction (STJ), and ascending aorta (AA). Of 1427 patients with BAV (45.2 ± 18.1 years, 71.9% men), 794 (55.6%) were Europeans and 633 (44.4%) were Asians. The groups were comparable in age and proportion of male sex. Asians had higher prevalence of type 1 BAV with raphe between right and non-coronary cusps than Europeans (19.7% vs. 13.6%, respectively; P < 0.001), whereas the Europeans had higher prevalence of type 0 BAV (two commissures, no raphe) than Asians (14.5% vs. 6.8%, respectively; P < 0.001). The prevalence of moderate and severe aortic regurgitation was higher in Europeans than Asians (44.2% vs. 26.8%, respectively; P < 0.001) whereas there were no differences in BAV with normal function or aortic stenosis. After adjusting for demographics, comorbidities, and valve function, the dimensions of the aortic annulus [mean difference 1.17 mm/m2, 95% confidence interval (CI) 0.96-1.39], SOV (mean difference 1.86 mm/m2, 95% CI 1.47-2.24), STJ (mean difference 0.52 mm/m2, 95% CI 0.14-0.90) and AA (mean difference 1.05 mm/m2, 95% CI 0.57-1.52) were significantly larger among Asians compared with Europeans.

Conclusions: This large multicentre registry reports for the first time that Asians with BAV showed more frequently type 1 BAV (with fusion between right and non-coronary cusp) and have larger aortic dimensions than Europeans. These findings have important implications for prosthesis type and size selection for TAVR.
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http://dx.doi.org/10.1093/eurheartj/ehx562DOI Listing
April 2018