Papers by Pim van der Harst
Journal of the American College of Cardiology
International Journal of Cardiology
Circulation: Cardiovascular Genetics, 2017
Myocardial infarction (MI) is one of the leading causes of global morbidity and mortality. Althou... more Myocardial infarction (MI) is one of the leading causes of global morbidity and mortality. Although the survival after MI has improved because of ameliorated treatment strategies, including primary percutaneous interventions, the long-term outcome of MI in general remains poor with a 1-year risk for recurrent cardiovascular disease of >10%. 1 Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term prognosis after MI. 2,3 However, treatment options for LV dysfunction are limited, and the biochemical mechanisms driving functional decline of the myocardium after MI are largely unknown. See Clinical Perspective Metformin, which is commonly used in the treatment of diabetes mellitus and more recently in insulin-resistant conditions, has been found to preserve LVEF and to reduce ISZ in nondiabetic animal models of MI. 4 The GIPS-III clinical trial (Glycometabolic Intervention as Adjunct to Primary Background-Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. Methods and Results-Participants were patients with ST-segment-elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (β=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10 −4) and ISZ (β=−0.41 [95% CI, −0.60 to −0.21]; P=3.2×10 −5). In addition, 24 hours post-MI measurements of medium HDL-TG (β=−0.40 [95% CI, −0.60 to −0.20]; P=6.4×2×10 −5), small HDL-TG (β=−0.34 [95% CI, −0.53 to −0.14]; P=7.3×10 −4), and the triglyceride content of very large HDL (β=−0.38 [95% CI, −0.58 to −0.18]; P=2.7×10 −4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10 −5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10 −4). Conclusions-HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles.
PloS one, 2016
Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numero... more Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4...
Interactive CardioVascular and Thoracic Surgery, 2016
OBJECTIVES: A thorough understanding of mitral and aortic valve motion dynamics is essential in m... more OBJECTIVES: A thorough understanding of mitral and aortic valve motion dynamics is essential in mastering the skills necessary for performing successful valve intervention (open or transcatheter repair or replacement). We describe a reproducible and versatile beatingheart mitral and aortic valve assessment and valve intervention training model in human cadavers. METHODS: The model is constructed by bilateral ligation of the pulmonary veins, ligation of the supra-aortic arteries, creating a shunt between the descending thoracic aorta and the left atrial appendage with a vascular prosthesis, anastomizing a vascular prosthesis to the apex and positioning an intra-aortic balloon pump (IABP) in the vascular prosthesis, cross-clamping the descending thoracic aorta, and finally placing a fluid line in the shunt prosthesis. The left ventricle is filled with saline to the desired pressure through the fluid line, and the IABP is switched on and set to a desired frequency (usually 60-80 bpm). Prerepair valve dynamic motion can be studied under direct endoscopic visualization. After assessment, the IABP is switched off, and valve intervention training can be performed using standard techniques. RESULTS: This high-fidelity simulation model has known limitations, but provides a realistic environment with an actual beating (human) heart, which is of incremental value. The model provides a unique opportunity to fill a beating heart with saline and to study prerepair mitral and aortic valve dynamic motion under direct endoscopic visualization. CONCLUSIONS: The entire setup provides a versatile beating-heart mitral and aortic valve assessment model, which may have important implications for future valve intervention training.
International Journal of Cardiology, 2017
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Journal of the American College of Cardiology, 2016
Circulation, Nov 25, 2014
eLife, May 10, 2016
Genetic variants identified by genome-wide association studies explain only a modest proportion o... more Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mous...
Heart (British Cardiac Society), Jul 15, 2016
Lifetime risk for cardiovascular (CV) disease is high but predicting incident events on an indivi... more Lifetime risk for cardiovascular (CV) disease is high but predicting incident events on an individual level remains difficult. Single measurements of galectin-3, a marker of tissue fibrosis, predict mortality and new-onset heart failure (HF). Persistently elevated levels may indicate a clinically silent disease process. Our aim was to establish the value of serial galectin-3 measurements to predict CV outcomes in the general population. Plasma galectin-3 was measured in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study at baseline and after ∼4 years. Changes in serial galectin-3 were expressed as categorical changes or absolute change from baseline and were related to subsequent outcome. Serial galectin-3 was measured in 5958 subjects (mean age 49±12 years; 49% female). The median duration of follow-up was 8.3 years. Persistently elevated galectin-3 (defined as highest quartile at baseline and highest quartile during visit 2, n=757 subjects) was associated with ...
PLoS genetics, May 1, 2016
Failure of the human heart to maintain sufficient output of blood for the demands of the body, he... more Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). ...
International journal of cardiology, Jan 10, 2015
Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and ... more Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and renal disease. Our aim is to describe miRNA levels related to early worsening renal function in acute HF patients. We studied the association between 12 circulating miRNAs and Worsening Renal Function (WRF; defined as an increase in the serum creatinine level of 0.3mg per deciliter or more from admission to day 3), absolute change in creatinine and Neutrophil Gelatinase Associated Lipocalin (NGAL) from admission to day 3 in 98 patients hospitalized for acute HF. At baseline, circulating levels of all miRNAs were lower in patients with WRF, with statistically significant decreased levels of miR-199a-3p, miR-423-3p, and miR-let-7i-5p (p-value<0.05). The increase in creatinine during the first 3days of hospitalization was significantly associated with lower levels of miR-199a-3p, miR-27a-3p, miR-652-3p, miR-423-5p, and miR-let-7i-5p, while the increase in NGAL was significantly associate...
International journal of epidemiology, Jan 24, 2015
PLOS ONE, 2015
Background Although erythropoietin has been used for decades in the treatment of anemia, data reg... more Background Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population.
European journal of heart failure, 2015
Molecular vision, 2009
Great variation exists in the age of onset of symptoms and the severity of disease at a given age... more Great variation exists in the age of onset of symptoms and the severity of disease at a given age in patients with retinitis pigmentosa (RP). The final pathway for this disease may involve apoptotic photoreceptor cell death. Telomere length is associated with biologic aging, senescence, and apoptosis. We evaluated whether the length of telomeres in leukocytes correlated with the severity of RP in patients with the Pro23His rhodopsin mutation who have shown marked heterogeneity in disease severity. We evaluated 122 patients with the Pro23His rhodopsin mutation. The patients' retinal function was stratified according to their 30-Hz cone electroretinogram (ERG). The length of telomeres in leukocytes was measured by the quantitative real time polymerase chain reaction (qRT-PCR) method in the 15 patients with the highest age-adjusted 30-Hz ERG amplitudes and in the 15 patients with the lowest amplitudes. Mean leukocyte telomere length was similar in the 15 patients with the highest c...
Objectives This study sought to test the hypothesis that patients with chronic heart failure (CHF... more Objectives This study sought to test the hypothesis that patients with chronic heart failure (CHF) have shorter telomeres compared with age-balanced and gender-balanced healthy individuals. Background Telomere length is considered to be a marker of biological aging. Chronic heart failure might be viewed as a condition associated with accelerated biological aging. Methods The telomere length ratio of leukocytes was determined prospectively by a quantitative polymerase chain reaction-based method in a case-control setting involving 803 participants: 183 healthy individuals and 620 CHF patients, ages 40 to 80 years, New York Heart Association functional class II to IV, and left ventricular ejection fraction of 0.40 or less. Results The median telomere length ratio was 0.64 (interquartile range [IQR] 0.47 to 0.88) in CHF patients compared with 1.05 (IQR 0.86 to 1.29) in control patients (p Ͻ 0.001). The telomere length ratio in CHF patients related to severity of disease (median value [IQR] of patients with New York Heart Association class II, III, or IV function was 0.67 [0.48 to 0.92], 0.63 [0.46 to 0.86], and 0.55 [0.46 to 0.75], respectively; p for trend Ͻ0.05). In addition, telomeres were shorter in patients with an ischemic compared with a nonischemic etiology of CHF. Patients with none, 1 (coronary, cerebral, or peripheral vascular disease), 2 (any combination of the previous), or 3 atherosclerotic manifestations had a median (IQR) telomere length of 0.72 (0.51 to 1.01), 0.65 (0.48 to 0.87), 0.48 (0.39 to 0.72), and 0.43 (0.27 to 0.67), respectively (p for trend Ͻ0.001). Conclusions Telomere length is shorter in patients with CHF compared with age-balanced and gender-balanced control patients, and related to the severity of disease. In addition, telomere length was incrementally shorter according to the presence and extent of atherosclerotic disease manifestations.
Atherosclerosis, Jan 24, 2015
The aim of this study is to determine sex differences in long-term outcome after coronary artery ... more The aim of this study is to determine sex differences in long-term outcome after coronary artery bypass grafting (CABG). The international randomized controlled IMAGINE study included 2553 consecutive patients with a left ventricular ejection fraction of >40% who underwent isolated CABG. Median follow-up was 32 months (IQR 17-42 months). The composite endpoint comprised of death, myocardial infarction (MI), cerebrovascular event, angina, revascularization and congestive heart failure. Cox regression analysis was used to examine sex differences in outcome post-CABG. Of the 2553 patients, 2229 were men and 324 (13%) were women. Women were older and more often reported diabetes and hypertension. Smoking and impaired renal function were more prevalent in men. Women experienced a higher event rate during follow-up (composite endpoint 18% vs 12%; P = 0.007). Cox regression showed an increased risk of the composite endpoint in women after adjustment for age (HR 1.48 (95% CI: 1.11-1.97))...
International Journal of Epidemiology, 2014
Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its appli... more Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra-and inter-batch variation between laboratories and techniques. Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However,
Nephrology Dialysis Transplantation, 2010
tested the hypothesis that the common variants in the candidate genes coding for the atrial natri... more tested the hypothesis that the common variants in the candidate genes coding for the atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) (NNPA and NPPB) are associated with blood pressure [1]. Firstly, in 1705 subjects from a general population cohort, 13 variants (single-nucleotide polymorphisms, SNPs) in this genetic locus were selected for association with higher ANP and BNP levels. Subsequently, a meta-analysis involving 14 743 Caucasian subjects confirmed the association for three SNPs. Next, in 29 717 subjects, these SNPs were found to be associated with lower blood pressure and lower risk for hypertension. The strongest effects were found for the SNPs coded rs5068 (minor allele frequency 6%) and rs198358 (19%) with reductions per allele of 0.9-1.5 mmHg systolic blood pressure (SBP) and 0.3-0.8 mmHg diastolic blood pressure (DBP), and odds ratios for hypertension of 0.85 and 0.90, respectively. The Global Blood Pressure Genetics (Global BPgen) consortium performed a genome-wide association study (GWAS) of 2.5 million tested and imputed SNPs for association with blood pressure in 34 433 subjects from population-based cohorts (Newton-Cheh et al., doi: 10.1038/ ng.361) [2]. Firstly, GWAS identified two SNPs reaching genome-wide significance (i.e. P < 5 × 10 −7) and 24 SNPs just below genome-wide significance. Next, 12 SNPs were selected for confirmation by direct genotyping in an additional 71 225 European subjects, and 10 loci were tested in silico in the populations of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Thus, eight SNPs were confirmed. Of these SNPs, the minor allele frequency was 9% or higher, the effect size per allele was up to 1.16 mmHg and r 2 ranged from 0.03 to 0.09. The aggregate effect accounted for~2 mmHg, and loci for higher or lower blood pressure were also associated with elevated or reduced risk for hypertension as a dichotomous trait. Genes nearby these lead SNPs emerge as new candidate genes for blood pressure. Among many (>30) others, these include CYP17A1 (steroid metabolism),
Uploads
Papers by Pim van der Harst