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Background In low-resource regions, fibrinolytic therapy is often the only option for ST-elevation myocardial infarction (STEMI) patients as primary percutaneous coronary intervention (PCI) is often not available and patients are hardly transferred to a medical center with PCI capacity within the first 120 minutes. Chronic kidney disease (CKD) is one of the most frequently encountered complications of STEMI. However, th

Aims: We aimed to determine whether in children with dilated cardiomyopathy repeated measurement of known risk factors for death or heart transplantation (HTx) during disease progression can identify children at the highest risk for adverse outcome. Methods and results: Of 137 children we included in a prospective cohort, 36 (26%) reached the study endpoint (SE: all-cause death or HTx), 15 (11%) died at a median of 0.09 years [inter-quartile range (IQR) 0.03–0.7] after diagnosis, and 21 (15%) underwent HTx at a median of 2.9 years [IQR 0.8–6.1] after diagnosis. Median follow-up was 2.1 years [IQR 0.8–4.3]. Twenty-three children recovered at a median of 0.6 years [IQR 0.5–1.4] after diagnosis, and 78 children had ongoing disease at the end of the study. Children who reached the SE could be distinguished from those who did not, based on the temporal evolution of four risk factors: stunting of length growth (−0.42 vs. −0.02 length Z-score per year, P < 0.001), less decrease in N-terminal pro-B-type natriur

Background: Prognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF. Methods: Four prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration. Results: 3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF < 40%), 588 as having HF with midrange EF (HFmrEF; EF 40–49%), and 621 as having HF with preserved EF (HFpEF; EF ≥ 50%). A total of 11 readily available variables built up the prognostic index. For four of these predictor variables, namely systolic blood pressure, serum creatinine, myocardial infarction, and diabetes, the effect differed across the three HF phenotypes. With a weighted IECV-adjusted AUC of 0.79 (0.74–0.83) for HFrEF, 0.74 (0.70–0.79) for HFmrEF, and 0.74 (0.71–0.77) for HFpEF, the model showed excellent discrimination. Moreover, there was a good agreement between the average observed and predicted 1-year mortality risks, especially after recalibration of the baseline mortality risks. Conclusions: Our HF phenotype stratified model showed excellent generalizability across four European cohorts and may provide a useful tool in HF phenotype-specific clinical decision-making.

Since the outbreak of SARS-CoV-2, also known as COVID-19, conflicting theories have circulated on the influence of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID-19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID-19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID-19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality.

Background: Coronary calcification has been linked to cardiovascular events. We developed and validated an algorithm to automatically quantify coronary calcifications on intravascular ultrasound (IVUS). We aimed to assess the prognostic value of an IVUS-calcium score (ICS) on patient-oriented composite endpoint (POCE). Methods: We included patients that underwent coronary angiography plus pre-procedural IVUS imaging. The ICS was calculated per patient. The primary endpoint was a composite of all-cause mortality, stroke, myocardial infarction, and revascularization (POCE). Results: In a cohort of 408 patients, median ICS was 85. Both an ICS ≥ 85 and a 100 unit increase in ICS increased the risk of POCE at 6-year follow-up (adjusted hazard ratio (aHR) 1.51, 95%CI 1.05–2.17, p value = 0.026, and aHR 1.21, 95%CI 1.04–1.41, p value = 0.014, respectively). Conclusions: The ICS, calculated by a validated automated algorithm derived from routine IVUS pullbacks, was strongly associated with the long-term risk of POCE. Graphical abstract: [Figure not available: see fulltext.].

Background Detailed insights in temporal evolution of high-sensitivity cardiac troponin following acute coronary syndrome (ACS) are currently missing. We aimed to describe and compare the post-ACS kinetics of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT), and to determine their intra- and interindividual variation in clinically stable patients. Methods and Results We determined hs-cTnI (Abbott) and hs-cTnT (Roche) in 1507 repeated blood samples, derived from 191 patients with ACS (median, 8/patient) who remained free from adverse cardiac events during 1-year follow-up. Post-ACS kinetics were studied by linear mixed-effect models. Using the samples collected in the 6- to 12-month post-ACS time frame, patients were then considered to have chronic coronary syndrome. We determined (differences between) the average hs-cTnI and average hs-cTnT concentration, and the intra- and interindividual variation for both biomarkers. Compared with hs-cTnT, hs-cTnI peaked higher (median 3506 ng/L versus 494 ng/L; P<0.001) and was quicker below the biomarker-specific upper reference limit (16 versus 19 days; P<0.001). In the post-6-month samples, hs-cTnI and hs-cTnT showed modest correlation (rspearman=

With innovations in therapeutic technologies and changes in population demographics, transcatheter interventions for structural heart disease have become the preferred treatment and will keep growing. Yet, a thorough clinical selection and efficient pathway from diagnosis to treatment and follow-up are mandatory. In this review we reflect on how artificial intelligence may help to improve patient selection, pre-procedural planning, procedure execution and follow-up so to establish efficient and high quality health care in an increasing number of patients.

Purpose: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. Methods: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40–50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. Results: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8–31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. Conclusions: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Background: Single high-sensitivity troponin T (hs-TnT) measurement is predictive of cardiac events in adults with congenital heart disease (ACHD). We aimed to study the prognostic value of serial hs-TnT measurements in stable patients with ACHD. Methods: In total, 602 consecutive patients with ACHD were enrolled in this prospective study (2011-2013). Blood sampling was performed at enrollment and thereafter yearly during scheduled visits, up to 4 years. Hs-TnT, N-terminal pro B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured. The composite primary endpoint was defined as all-cause mortality, heart failure, arrhythmia, hospitalization, cardiac (re)interventions, or thromboembolic events. The relationship between changes in serial hs-TnT and the primary endpoint was studied by joint models with adjustment for repeated NT-proBNP and eGFR. Results: In 601 patients (median age, 33 [interquartile range, 25-41] years, 42% women, 90% NYHA I), at least 1 hs-TnT measurement was performed; a mean of 4.3 hs-TnT measurements per patient were collected. After a median follow-up of 5.8 [interquartile range, 5.3-6.3] years, 229 (38.1%) patients reached the primary endpoint. On average, hs-TnT levels increased over time, and more in patients who reached the primary endpoint (P < 0.001). A 2-fold higher hs-TnT was associated with the primary endpoint (unadjusted hazard ratio, 1.62; 95% confidence interval, 1.44-1.82; P < 0.001). The association remained after adjustment for repeated eGFR but not when adjusted for repeated NT-proBNP; repeated NT-proBNP remained associated with the primary endpoint. Conclusion: In stable patients with ACHD, hs-TnT levels increased before the occurrence of an event and repeated hs-TnT was associated with the risk of adverse cardiac events. However, repeated hs-TnT was not superior to repeated NT-proBNP., Contexte : Le dosage unique de la troponine T hypersensible (hs-TnT) est predictif d ’ev enements cardiaques chez les adultes atteints de cardiopathie congenitale. Notre objectif etait d ’etudier la valeur pro- nostique du dosage seriel de la hs-TnT chez des patients adultes atteints de cardiopathie congenitale qui pr esentaient un etat stable. Methodologie : Au total, 602 patients adultes atteints de cardiopathie congenitale ont et e inscrits cons ecutivement à cette etude prospective (2011-2013). Les prelèvements sanguins ont et e effectu es au moment de l’inscription et chaque annee par la suite au cours des visites prevues, jusqu ’à la quatrième annee. La hs-TnT, le propeptide natriuretique de type B N-terminal (NT-proBNP) et le taux de filtration glomerulaire estim e (TFGe) ont et e mesur es. Le paramètre d’evaluation principal regroupait les d ecès toutes causes confondues, l’insuffisance cardiaque, l’arythmie cardiaque, les hospitalisations, les (re)interventions cardiaques et les ev enements thromboemboliques. La relation entre les variations des taux seriels de hs-TnT et le paramètre d’evaluation principal a et e etudi ee à l ’aide de modèles conjoints corriges pour tenir compte de la mesure r ep et ee du taux de NT-proBNP et du TFGe. Resultats : Chez 601 patients (âge median : 33 ans [intervalle inter- quartile : 25-41 ans], 42 % de sexe feminin, 90 % pr esentant une maladie de classe I de la NYHA), au moins un dosage de la hs-TnT a et e effectu e; les investigateurs ont effectu e, en moyenne, 4,3 dosages de la hs-TnT par patient. Au terme d’un suivi median de 5,8 ans [intervalle interquartile : 5,3-6,3 ans], le paramètre d’evaluation prin- cipal a et e atteint chez 229 (38,1 %) patients. En

Objective: To examine the strength of the association between exercise capacity and health-related quality of life (HRQOL) during and after cardiac rehabilitation (CR) in patients with acute coronary syndrome (ACS) who completed CR. Design: Prospective cohort study. Setting: Outpatient CR center. Participants: Patients (N=607) with ACS who completed CR. Interventions: Multidisciplinary 12-week exercise-based CR program. Main Outcome Measures: At baseline (pre-CR), the 6-Minute Walk Test (6MWT) was performed to determine exercise capacity, and the MacNew Heart Disease Health-related Quality of Life questionnaire was used to assess HRQOL. Measurements were repeated immediately after completion of CR (post-CR): at 12 months and 18 months follow-up. Multivariable linear regression, including an interaction term for time and exercise capacity, was applied to study the association between exercise capacity and HRQOL at different time points relative to CR, whereas model parameters were estimated by methods that accounted for dependency of repeated observations within individuals. Results: Mean age in years ± SD was 58±8.9 and 82% of participants were male. Baseline mean 6MWT distance in meters ± SD was 563±77 and median (25th-75th percentile) global HRQOL was 5.5 (4.6-6.1) points. Mean 6MWT distance (P<.001) and the global (P<.001), physical (P<.001), emotional (P<.001) and social (P<.001) domains of HRQOL improved significantly during CR and continued to improve during follow-up post-CR. Independent of the timing relative to CR (ie, pre-CR, post-CR, or during follow-up), a difference of 10 m 6MWT distance was associated with a mean difference in the global HRQOL domain of 0.007 (95% confidence interval [CI], 0.001-0.014) points (P=.029) and a mean difference in the physical domain of 0.009 (95% CI, 0.001-0.017) points (P=.023). Conclusions: Better exercise capacity was significantly associated with higher scores on the global and physical domains of HRQOL, irrespective o

__Aims:__ Health insurance claims (HIC) databases in the Netherlands capture unselected patient populations, which makes them suitable for epidemiological research on sex differences. Based on a HIC database, we aimed to reveal sex differences in heart failure (HF) outcomes, with particular focus on co-morbidities and medication. __Methods and results:__ The Achmea HIC database included 14 517 men and 11 259 (45%) women with a diagnosis treatment code for chronic HF by January 2015. We related their sex, co-morbidities, and medication adherence (medication possession rate >0.8) with the primary endpoint (PE) of all-cause mortality or HF admission during a median follow-up of 3.3 years, using Cox regression. Median age of men and women was 72 and 76 years, respectively. Prevalence of co-morbidities and use of disease-modifying drugs was higher in men; however, medication adherence was similar. At the end of follow-up, 35.1% men and 31.8% women had reached the PE. The adjusted hazard ratio for men was 1.25 (95% confidence interval: 1.19–1.30). A broad range of co-morbidities was associated with the PE. Overall, these associations were stronger in women than in men, particularly for renal insufficiency, chronic obstructive pulmonary disease/asthma, and diabetes. Non-adherence to disease-modifying drugs was related with a higher incidence of the PE, with similar effects between sexes. __Conclusions:__ In a representative sample of the Dutch population, as captured in a HIC database, men with chronic HF had a 25% higher incidence of death or HF admission than women. The impact of co-morbidities on the outcome was sex dependent, while medication adherence was not.

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

Background: Staging of atrial fibrillation (AF) is essential to understanding disease progression and the accompanied increase in therapy failure. Blood-based heat shock protein (HSP) levels may enable staging of AF and the identification of patients with higher risk for AF recurrence after treatment. Objective: This study evaluates the relationship between serum HSP levels, presence of AF, AF stage and AF recurrence following electrocardioversion (ECV) or pulmonary vein isolation (PVI). Methods: To determine HSP27, HSP70, cardiovascular (cv)HSP and HSP60 levels, serum samples were collected from control patients without AF and patients with paroxysmal atrial fibrillation (PAF), persistent (PeAF) and longstanding persistent (LSPeAF) AF, presenting for ECV or PVI, prior to intervention and at 3-, 6- and 12-months post-PVI. Results: The study population (n = 297) consisted of 98 control and 199 AF patients admitted for ECV (n = 98) or PVI (n = 101). HSP27, HSP70, cvHSP and HSP60 serum levels did not differ between patients without or with PAF, PeAF or LSPeAF. Additionally, baseline HSP levels did not correlate with AF recurrence after ECV or PVI. However, in AF patients with AF recurrence, HSP27 levels were significantly elevated post-PVI relative to baseline, compared to patients without recurrence. Conclusions: No association was observed between baseline HSP levels and the presence of AF, AF stage or AF recurrence. However, HSP27 levels were increased in serum samples of patients with AF recurrence within one year after PVI, suggesting that HSP27 levels may predict recurrence of AF after ablative therapy

OBJECTIVE: To investigate the relation between body mass index class and changes in health-related quality of life in patients participating in cardiac rehabilitation. DESIGN: Prospective cohort study. PATIENTS: A total of 503 patients with acute coronary syndrome. METHODS: Data from the OPTICARE trial were used, in which health-related quality of life was measured with the MacNew Heart Disease HRQOL Instrument at the start, directly after, and 9 months after completion of cardiac rehabilitation. Patients were classed as normal weight, overweight, or obese. RESULTS: During cardiac rehabilitation, global health-related quality of life improved in patients in all classes of body mass index. Patients classed as overweight had a significantly greater improvement in social participation than those classed as normal weight (5.51-6.02 compared with 5.73-5.93, respectively; difference in change 0.30, p = 0.025). After completion of cardiac rehabilitation, health-related quality of life continued to improve similarly in patients in all classes of body mass index. CONCLUSION: Health-related quality of life improved during cardiac rehabilitation in patients of all classes of body mass index. Patients classed as overweight showed the greatest improvement. The beneficial effects were maintained during extended follow-up after completion of cardiac rehabilitation.

Background: Complete revascularization in patients with an acute coronary syndrome and multivessel disease is superior compared to culprit-only treatment. However, it is unknown whether direct complete or staged complete revascularization should be pursued. Methods: The BIOVASC study is an investigator-initiated, prospective, multicenter, randomized, 2-arm, international, open-label, noninferiority trial. We will randomize 1,525 patients 1:1 to immediate complete revascularization (experimental arm) or culprit-only plus staged complete revascularization (control arm). Patients will be enrolled in approximately 30 sites in Belgium, Italy, the Netherlands, and Spain. The primary end point is a composite of all-cause mortality, nonfatal myocardial infarction, any unplanned ischemia-driven revascularization (excluding staged procedures in the control arm at the predetermined time), and cerebrovascular events (MACCE) at 1 year post index procedure. Conclusions: The BIOVASC study aims to further refine the treatment algorithm for acute coronary syndrome patients with multivessel disease in terms of optimal timing for complete revascularization (Clinicaltrials.gov NCT03621501).

Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARSCoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.

AIMS: The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. METHODS AND RESULTS: In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress - parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan-Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5-34.0), age at TOF repair 0.9 years (0.6-2.1)]. After a median follow-up of 8.6 years (6.7-14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (-17 ± 15 vs. -26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5-43.7; P = 0.001) as predictor for the composite endpoint. CONCLUSION: An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.

Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n=64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2–139.9), 118.9 (109.3–147.7), 118.3 (106.8–130.1) versus 108.0 (102.3–115.2) pM, respectively, p all <0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32–58) months. Kaplan–Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2–4 (Mean survival times were 46 (95% CI: 30–65) versus 68 (58–77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1–11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.

Background: We sought to assess the effects of percutaneous atrial septal defect (ASD) closure on blood biomarker levels that possibly reflect reverse cardiac remodeling. Therefore, this study investigated temporal changes in six blood biomarkers following percutaneous ASD closure in adults. Methods: In this prospective observational cohort study, adults with ASD type II scheduled for percutaneous closure were included (2012–2016). N

Background: Population means of conventional cardiovascular biomarkers are known to differ between ethnic groups. In this study we performed detailed comparisons in the temporal pattern of these biomarkers between Caucasian and Chinese diabetic patients with acute coronary syndrome (ACS). Methods: We studied differences in temporal changes of established cardiovascular biomarkers, including high-density lipoprotein (HDL), low-density lipoprotein (LDL)

Trastuzumab prolongs progression-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, trastuzumab treatment is hampered by cardiotoxicity, defined as a left ventricular ejection fraction (LVEF) decline with a reported incidence ranging from 3 to 27% depending on variable factors. Early identification of patients at increased risk of trastuzumab-induced myocardial damage is of great importance to prevent deterioration to irreversible cardiotoxicity. Although current cardiac monitoring with multi gated acquisition (MUGA) scanning and/or conventional 2D-echocardiography (2DE) have a high availability, their reproducibility are modest, and more sensitive and reliable techniques are needed such as 3D-echocardiography (3DE) and speckle tracking echocardiography (STE). But which other diagnostic imaging modalities are available for patients before and during trastuzumab treatment? In addition, what is the optimal frequency and duration of cardiac monitoring? At last, which biomarker monitoring strategies are currently available for the identification of cardiotoxicity in patients treated with trastuzumab?

Background: Population means of conventional cardiovascular biomarkers are known to differ between ethnic groups. In this study we performed detailed comparisons in the temporal pattern of these biomarkers between Caucasian and Chinese diabetic patients with acute coronary syndrome (ACS). Methods: We studied differences in temporal changes of established cardiovascular biomarkers, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, cardiac Troponin T (TnT), NT-proBNP and C-reactive protein (CRP), in 48 Chinese and 48 clinically matched Caucasian patients with type 2 diabetes mellitus who were admitted for ACS. Blood samples were collected at regular time intervals during 30 days to 1 year after the index ACS. Results: In the >30 day post ACS period, mean serum levels of LDL (2.16 vs. 1.47 mmol/L; p-value <0.001), total cholesterol (4.08 vs. 3.11 mmol/L; p-value <0.001), TnT (11.0 vs. 7.76 ng/L; p-value 0.010) and CRP (2.0 vs. 0.78 mg/L; p-value <0.001) were systematically higher in Caucasian than in Chinese patients. HDL and NT-proBNP levels were similar. Conclusions: Our study showed clinically relevant differences in levels of established cardiovascular biomarkers between Caucasian and Chinese post ACS patients. Further cross-ethnic studies are warranted to determine secondary prevention treatment biomarker targets in specific populations.

The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Data 1 file, in which additional delimiters were included in the first column for a number of rows, resulting in column shifts for some of these rows. The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found as Supplementary Information associated with this Correction. In addition, the original version of this Article contained an error in the author affiliations. An affiliation of Abdel Abdellaoui with Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Background: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. Methods and findings: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8- 9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109- 131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also s

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps: estimating a multivariate mixed model for the longitudinal outcomes and then using the output from this model to fit the survival submodel. So-called two-stage approaches have previously been proposed and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings.

OBJECTIVES: Our goal was to report the long-term serial follow-up after transatrial-transpulmonary repair of tetralogy of Fallot (TOF) and to describe the influence of the timing of the repair on outcome. METHODS: We included all patients with TOF who had undergone transatrial-transpulmonary repair between 1970 and 2012. Records were reviewed for patient demographics, operative details and events during the follow-up period (death, pulmonary valve replacement, cardiac reinterventions and hospitalization/intervention for arrhythmias). In patients with elective early primary repair of TOF after 1990, a subanalysis of the optimal timing of TOF repair was performed. RESULTS: A total of 453 patients were included (63% male patients; 65% had transannular patch); 261 patients underwent primary elective repair after 1990. The median age at TOF repair was 0.7 years (25th-75th percentile 0.3-1.3) and decreased from 1.7 to 0.4 years from before 1990 to after 2000, respectively (P < 0.001). The median follow-up duration after TOF repair was 16.8 years (9.6-24.7). Events developed in 182 (40%) patients. In multivariable analysis, early repair of TOF (<6 months) [hazard ratio (H

Aims: Evidence on the association of macrophage- and neutrophil-related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C-reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF). Methods and Results: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine-rich type 1 protein M130 (CD163), tartrate-resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin-1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow-up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event-free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow-up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1-standard deviation change in biomarker]: CD163 [2.07(1.47–2.98), P < 0.001], TRAP [0.62 (0.43–0.90), P = 0.009], GRN [2.46 (1.64–3.84), P < 0.001], SPON1 [3.94 (2.50–6.50), P < 0.001], and PGLYRP1 [1.62 (1.14–2.31), P = 0.006]. Conclusions: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF.

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and 5

Background Sex differences in efficacy and safety of dual antiplatelet therapy remain uncertain because of the underrepresentation of women in cardiovascular trials. The aim of this study was to perform a sex-specific analysis of the pooled efficacy and safety data of clinical trials comparing a high potent P2Y12 inhibitor+aspirin with clopidogrel+aspirin in patients with acute coronary syndrome. Methods and Results A systematic literature search was performed. Randomized clinical trials that compared patients following percutaneous coronary intervention/acute coronary syndrome who were taking high potent P2Y12 inhibitors+aspirin versus clopidogrel+aspirin were selected. Random effects estimates were calculated and relative risks with 95% CIs on efficacy and safety end points were determined per sex. We included 6 randomized clinical trials comparing prasugrel/ticagrelor versus clopidogrel in 43 990 patients (13 030 women), with a median follow-up time of 1.06 years. Women and men had similar relative risk (RR) reduction for major cardiovascular events (women: RR, 0.89 [95% CI, 0.80-1.00; men: RR, 0.84 [95% CI, 0.79-0.91) (P for interaction=0.39). Regarding safety, women and men had similar risk of major bleeding by high-potency dual antipl

Background: Renal transplant patients have a high peri-operative risk for cardiovascular events. Pre-operative screening for cardiac ischaemia might lower this risk, but there are no specific guidelines. Methods: We conducted a chart review for all renal transplants performed between January 2010 and December 2013. We collected data about patient characteristics, pre-operative cardiac evaluation before referral, diagnostic tests and interventions. Logistic regression analyses were then applied to relate these factors to the composite endpoint of cardiac death, myocardial infarction, coronary revascularisation or admission for heart failure within 3 months after transplantation. Results: A total of 770 kidney transplants were performed in 751 patients. In 750 cases (97%) a referral to the cardiologist was made. Non-invasive ischaemia detection by myocardial perfusion scintigraphy, exercise stress test or dobutamine stress echocardiography was carried out in 631 cases (82%). Coronary angiography was performed in 85 cases, which revealed significant coronary artery disease in 19 cases. Prophylactic revascularisation was done in 7 cases. The incidence of the study endpoint was 8.6%. In multivariable regression analysis, age at transplantation, pre-transplant myocardial infarction or heart failure, post-operative decrease in haemoglobin and positive non-invasive ischaemia testing were significantly associated with the study endpoint. However, when analysed separately, none of the different non-invasive ischaemia detection modalities were related to the study endpoint. Conclusion: Especially those renal transplant candidates with a cardiac history carry a high risk for a cardiovascular event post-transplantation. Uniformity in cardiac screening of renal transplant candidates and better pre-operative preparation might lower this post-operative risk. Besides, post-transplant anaemia should be prevented.

Objective: Despite its predictive value for mortality in various diseases, the relevance of growth differentiation factor-15 (GDF-15) as prognostic biomarker in pulmonary hypertension (PH) remains unclear. This study investigated the association between GDF-15 and outcomes in adults with PH. Methods: This is a single-centre prospective observational cohort study. All adults with PH were included at the day

AIMS: Cardiovascular magnetic resonance (CMR) imaging is an important tool in the assessment of paediatric cardiac disease. Reported reference values of ventricular volumes and masses in the paediatric population are based on small cohorts and several methodologic differences between studies exist. We sought to create steady-state free precession (SSFP) CMR reference values for biventricular volumes and mass by combining data of previously published studies and re-analysing these data in a standardized manner. METHODS AND RESULTS: A total of 141 healthy children (68 boys) from three European centres underwent cine-SSFP CMR imaging. Cardiac structures were manually contoured for end-diastolic and end-systolic phases in the short-axis orientation according to current standardized CMR post-processing guidelines. Volumes and masses were derived from these contours. Age-related reference curves were constructed using the lambda mu sigma method. Median age was 12.7 years (range 0.6-18.5). We report biventricular volumes and masses, unindexed and indexed for body surface area, stratified by age groups. In general, boys had approximately 15% higher biventricular volumes and masses compared with girls. Only in children aged <6 years old no gender differences could be observed. Left ventricle ejection fraction was slightly higher in boys in this study population (median 67% vs. 65%, P = 0.016). Age-related reference curves showed non-linear relations between age and cardiac parameters. CONCLUSION: We report volumetric SSFP CMR imaging reference values for children aged 0-18 years old in a relatively large multi-centre cohort. These references can be used in the follow-up of paedia

Growth differentiation factor-15 (GDF-15) has appeared as a promising biomarker with strong predictive abilities in acute coronary syndrome (ACS). However, studies are solely based on single measurements in the acute phase of an ACS event. The way GDF-15 patterns in post-ACS patients behave on the long term is largely unknown. We conducted a nested case-control study within our multicenter, prospective, observational biomarker study (BIOMArCS) of 844 ACS patients. Following an index ACS event, high-frequency blood sampling was performed during 1-year of follow-up. GDF-15 was determined batchwise by electrochemiluminescence immunoassays in 37 cases with a recurrent event during 1-year follow-up, and in 74 event-free controls. Cases and controls had a mean § standard deviation age of 66.9 § 11.3 years and 81% were men. From 30 days onwards, patients showed stable levels, which were on average 333 (95% confidence interval 68 to 647) pg/mL higher in cases than controls (1704 vs 1371 pg/mL; p value 0.013). Additionally, in the post 30-day period, GDF-15 showed low within-individual variability in both cases and controls. In conclusion, post-ACS patients experiencing a recurrent event had stable and systematically higher GDF-15 levels during 30-day to 1-year follow-up than their event-free counterparts with otherwise similar clinical characteristics. Thus, postdischarge blood sampling might be used throughout the course of 1 year to improve prognostication, whereas, in view of the low within-individual variation, the number of repeated sampling moments might be limited.

The Biomarker Study to Identify the Acute Risk of a Coronary Syndrome (BIOMArCS) is a prospective, observational study that has been designed to study the evolution of blood biomarkers in post-acute coronary syndrome (ACS) patients. In our recently published study “Temporal evolution of Myeloperoxidase and Galect

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: Fr

Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (P<0.001) and MACE (P<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (P=0.001) or chromosomal anomalies (P<0.001). MYH7 was involved in 48% of the sarcomere gene mutations. MYH7 and ACTC1 mutations had lower risk for MACE than MYBPC3 and TTN (P=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; P=0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis MYBPC3, TTN, arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients.

Background: Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. Aims: To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. Methods: The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including health

Objectives: Contradictory results have been reported regarding the association between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD). We assessed the cardiometabolic phenotype and prevalence of CVD in middle-aged women with PCOS, compared with age-matched controls from the general population, and estimated 10-year CVD risk and cardiovascular health score. Design: A cross-sectional study. Participants: 200 women aged >45 with PCOS, and 200 age-matched controls. Measurements: Anthropometrics, insulin, lipid levels, prevalence of metabolic syndrome and type II diabetes. Ten-year Framingham risk score and the cardiovascular health score were calculated, and carotid intima-media thickness (cIMT) was measured. Results: Mean age was 50.5 years (SD = 5.5) in women with PCOS and 51.0 years (SD = 5.2) in controls. Increased waist circumference, body mass index and hypertension were more often observed in women with PCOS (P <.001). In women with PCOS, the prevalence of type II diabetes and metabolic syndrome was not significantly increased and lipid levels were not different from controls. cIMT was lower in women with PCOS (P <.001). Calculated cardiovascular health and 10-year CVD risk were similar in women with PCOS and controls. Conclusions: Middle-aged women with PCOS exhibit only a moderately unfavourable cardiometabolic profile compared to age-matched controls, even though they present with an increased BMI and waist circumference. Furthermore, we found no evidence for increased (10-year) CVD risk or more severe atherosclerosis compared with controls from the general population. Long-term follow-up of women with PCOS is necessary to provide a definitive answer concerning long

Objectives: Prolonged emergency department to ICU waiting time may delay intensive care treatment, which could negatively affect patient outcomes. The aim of this study was to investigate whether emergency department to ICU time is associated with hospital mortality. Design, Setting, and Patients: We conducted a retrospective observational cohort study using data from the Dutch quality registry National Intensive Care Evaluation. Adult patients admitted to the ICU directly from the emergency department in six university hospitals, between 2009 and 2016, were included. Using a logistic regression model, we investigated the crude and adjusted (for disease severity; Acute Physiology and Chronic Health Evaluation IV probability) odds ratios of emergency department to ICU time on mortality. In addition, we assessed whether the Acute Physiology and Chronic Health Evaluation IV probability modified the effect of emergency department to ICU time on mortality. Secondary outcomes were ICU, 30-day, and 90-day mortality. Interventions: None. Measurements and Main Results: A total of 14,788 patients were included. The median emergency department to ICU time was 2.0 hours (interquartile range, 1.3–3.3hr). Emergency department to ICU time was correlated to adjusted hospital mortality (p < 0.002), in particular in patients with the highest Acute Physiology and Chronic Health Evaluation IV probability and long emergency department to ICU time quintiles: odds ratio, 1.29; 95% CI, 1.02–1.64 (2.4–3.7hr) and odds ratio, 1.54; 95% CI, 1.11–2.14 (> 3.7hr), both compared with the reference category (< 1.2hr). For 30-day and 90-day mortality, we found similar results. However, emergency department to ICU time was not correlated to adjusted ICU mortality (p = 0.20). Conclusions: Prolonged emergency department to ICU time (> 2.4hr) is asso

Antibodies to oxidized LDL (oxLDL) may be associated with improved outcomes in cardiovascular disease. However, analysis is restricted by heterogenous study design and endpoints. Our objective was to conduct a comprehensive systematic review assessing anti-oxLDL antibodies in relation to coronary artery disease (CAD). Through a systematic literature search, we identified all studies assessing the relationship of either, IgG or IgM ox-LDL/ copper-oxLDL/ malondialdehyde-LDL, with coronary atherosclerosis or cardiovascular events in populations with, and without, established CAD. Systematic review best practices were adhered to and study quality was assessed. An initial electronic database search identified 2059 records, which was subsequently followed by abstract and full-text review. Finally, we included 18 studies with over 1811 patients with CAD. The studies varied according to populations studied, conventional cardiovascular risk factors and interventional modalities used to assess CAD. IgM anti-oxLDL antibodies were found to indicate protection from more severe CAD and possibly cardiovascular events, whilst the relationship with IgG is more complex and difficult to elucidate, with studies reporting divergent results. In this systematic review, there is evidence that suggests a relationship between anti-oxLDL antibodies and CAD, especially for the IgM subclass. However, further studies, with well-characterized prospective cohorts, will be important to clarify these associations.

PURPOSE. Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements and recurrent mutated genes. The aim of this study was to investigate if copy number variations (CNV) alone and in combination with other genetic and clinico-histopathological variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM. METHODS. We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study (ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify molecular subclasses with distinct CNV patterns. The subclasses associate with mutational status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological data, and their combination for study endpoint risk. RESULTS. Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1, or EIF1AX were identified. The sample’s cluster allocation contributed significantly to mutational status of samples in predicting the incidence of metastasis during a median of 45.6 (interquartile range [IQR]: 24.7–81.8) months of follow-up (P < 0.05) and vice versa. Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100 months of follow-up. CONCLUSIONS. UM has distinct CNV patterns that correspond to different mutated driver genes. Incorporating clinico-histopathological, cluster and mutation data in the analysis results in good performance for UM-related DFS prediction.

Purpose: We assessed the temporal pattern of 29 immune and inflammatory proteins in post-acute coronary syndrome (ACS) patients, prior to the development of recurrent ACS. Methods: High-frequency blood sampling was performed in 844 patients admitted for ACS during one-year follow-up. We conducted a case-control study on the 45 patients who experienced reACS (cases) and two matched event-free patients (controls) per case. Olink Proteomics’ immunoassay was used to obtain serum levels of the 29 proteins, expressed in an arbitrary unit on the log2-scale (Normalized Protein eXpression, NPX). Linear mixed-effects models were applied to examine the temporal pattern of the proteins, and to illustrate differences between cases and controls. Results: Mean age was 66 ± 12 years and 80% were men. Cases and controls had similar baseline clinical characteristics. During the first 30 days, and after multiple testing correction, cases had significantly higher serum levels of CXCL1 (difference of 1.00 NPX, p ¼ 0.002), CD84 (difference of 0.64 NPX, p ¼ 0.002) and TNFRSF10A (difference of 0.41 NPX, p < 0.001) than controls. After 30 days, serum levels of all 29 proteins were similar in cases and controls. In particular, no increase was observed prior to reACS. Conclusions: Among 29 immune and inflammatory proteins, CXCL1, CD84 and TNFRSF10A were associated with early reACS after initial ACS-admission.

Objective Soluble suppression of tumourigenicity-2 (sST2) is upregulated as response to myocardial stress and may be a potential biomarker for risk stratification in patients with adult congenital heart disease (ACHD). This study aimed to investigate the release of sST2 and its association with cardiovascular events in ACHD. Methods In this prospective cohort study, 602 consecutive patients with ACHD visiting the outpatient clinic were included (2011–2013). The association between sST2 and a primary composite endpoint of all-cause mortality, heart failure, hospitalisation, arrhythmia, thromboembolic events or cardiac interventions was investigated using multivariable Cox regression. Results sST2 was measured in 590 (98%) patients (median age 33 [25–41] years, 42% women). After a median follow-up of 5.8 [IQR 5.1–6.2) years, 225 (38.5%) reached the primary endpoint. sST2 was significantly associated wit

Background Sex differences in acute coronary syndrome (ACS) have been reported, but little is known about the situation in the Netherlands. Me

Background: When the treatment effect on the outcome of interest is influenced by a baseline/demographic factor, investigators say that an interaction is present. In randomized clinical trials (RCTs), this type of analysis is typically referred to as subgroup analysis. Although interaction (or subgroup) analyses are usually stated as a secondary study objective, it is not uncommon that these results lead to changes in treatment protocols or even modify public health policies. Nonetheless, recent reviews have indicated that their proper assessment, interpretation and reporting remain challenging. Results: Therefore, this article provides an overview of these challenges, to help investigators find the best strategy for application of interaction analyses on binary outcomes in RCTs. Specifically, we discuss the key points of formal interaction testing, including the estimation of both additive and multiplicative interaction effects. We also provide recommendations that, if adhered to, could increase the clarity and the completeness of reports of RCTs. Conclusion: Altogether, this article provides a brief non-statistical guide for clinical investigators on how to perform, interpret and report interaction (subgroup) analyses in RCTs.

Background: D-dimers are generated during endogenous fibrinolysis of a blood clot and have a central role in diagnostic algorithms to rule out venous thromboembolism. HMG-CoA reductase inhibitors, more commonly called statins, are known to have effects independent of LDL-cholesterol lowering, including antithrombotic properties. An effect of statins on D-dimer levels has been reported in a prior systematic review and meta-analysis, but methodological shortcomings might have led to an overestimated effect. To re-evaluate the association between statins and D-dimer levels, we systematically reviewed all published articles on the influence of statins on D-dimer levels and conducted a novel meta-analysis (PROSPERO registration number CRD42017058932). Materials and methods: We electronically searched EMBASE, Medline Epub, Cochrane, Web of Science and Google Scholar (100 top relevance) (da

Studies with longitudinal measurements are common in clinical research. Particular interest lies in studies where the repeated measurements are used to predict a time‐to‐event outcome, such as mortality, in a dynamic manner. If event rates in a study are low, however, and most information is to be expected from the patients experiencing the study endpoint, it may be more cost efficient to only use a subset of the data. One way of achieving this is by applying a case‐cohort design, which selects all cases and only a random samples of the noncases. In the standard way of analyzing data in a case‐cohort design, the noncases who were not selected are completely excluded from analysis; however, the overrepresentation of the cases will lead to bias. We propose to include survival information o

AimsWe aim to study the feasibility and clinical value of pulmonary artery pressure monitoring with the CardioMEMS™device in order to optimize and guide treatment in patients with a HeartMate3left ventricular assist device (LVAD).Methods and resultsIn this single-centre, prospective pilot study, we will include10consecutive patients with New YorkHeart Association Class IIIb or IV with Interagency Registry for Mechanically Assisted Circulatory Support Classes2–5scheduledfor implantation of a HeartMate3LVAD. Prior to LVAD implantation, patients will receive a CardioMEMS sensor, for dailypulmonary pressure readings. The haemodynamic information provided by the CardioMEMS will be used to improvehaemodynamic status prior to LVAD surgery and optimize the timing of LVAD implantation. Post-LVAD implantation, thehaemodynamic changes will be assessed for additive value in detecting potential complications in an earlier stage (bleedingand tamponade). During the outpatient clinic phase, we will assess whether the haemodynamic feedback can optimize pumpsettings, detect potential complications, and further tailor the clinical management of these patients.ConclusionsThe HEMO-VAD study is thefirst prospective pilot study to explore the safety and feasibility of usingCardioMEMS for optimization of LVAD therapy with additional (remote) haemodynamic information.

Aims: In pre-hospital settings handled by paramedics, identification of patients with myocardial infarction (MI) remains challenging when automated electrocardiogram (ECG) interpretation is inconclusive. We aimed to identify those patients and to get them on the right track to primary percutaneous coronary intervention (PCI). Methods and results: In the Rotterdam-Rijnmond region, automated ECG devices on all ambulances were supplemented with a modem, enabling transmission of ECGs for online expert interpretation. The diagnostic protocol for acute chest pain was modified and monitored for 1 year. Patients with an ECG that met the criteria for ST-elevation myocardial infarction (STEMI) were immediately transported to a PCI hospital. ECGs that did not meet the STEMI criteria, but showed total ST deviation ≥800 µv were transmitted for online interpretation by the ECG expert. Online supervision was offered as a service if ECGs showed conduction disorders, or had an otherwise ‘suspicious’ pattern according to the ambulance paramedics. We enrolled 1,076 patients with acute ischaemic chest pain who did not meet the automated STEMI criteria. Their mean age was 63 years; 64% were men. After online consultation, 735 (68%) patients were directly transported to a PCI hospital for further treatment. PCI within 90 min was performed in 115 patients. Conclusion: During a 1-year evaluation of the modified pre-hospital triage protocol for patients with acute ischaemic chest pain, over 100 acute MI patients with an initially inconclusive ECG received primary PCI within 90 min. Because of these results, we decided to continue the operation of the modified protocol.