Publications by authors named "Arnoud van der Laarse"

103 Publications

Biochemical risk factors of atherosclerotic cardiovascular disease: from a narrow and controversial approach to an integral approach and precision medicine.

Expert Rev Cardiovasc Ther 2022 Jan 3:1-12. Epub 2022 Jan 3.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Guidelines of management of dyslipidemias and prevention of cardiovascular disease (CVD) are based on firm scientific evidence obtained by randomized controlled trials (RCTs). However, the role of elevated low-density lipoprotein-cholesterol (LDL-C)as a risk factor of CVD and therapies to lower LDL-C are frequently disputed by colleagues who disagree with the conclusions of the RCTs published. This review focuses on this dispute, and evaluates the current approach of management of dyslipidemias and CVD prevention to find modern alternatives for more precise diagnosis and therapy of dyslipidemic patients.

Areas Covered: Recent interest in lipoprotein(a) (Lp(a)) and remnants lipoproteins and in therapies that do not influence LDL-C levels primarily, such as anti-inflammatory drugs and icosapent ethyl, has revitalized our concern to optimize the care for patients with increased CVD risk without focusing simply on reduction of LDL-C by therapy with statins, ezitemibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors.

Expert Opinion: The limited characterization of study populations by measurement of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) followed by measurement or calculation of LDL-C should be extended by a more integral approach in order to realize precision diagnostics and precision medicine, for the sake of personalized patient care.
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http://dx.doi.org/10.1080/14779072.2021.2022475DOI Listing
January 2022

Association of apolipoproteins C-I, C-II, C-III and E with coagulation markers and venous thromboembolism risk.

Clin Epidemiol 2019 22;11:625-633. Epub 2019 Jul 22.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Apolipoproteins C-I, C-II, C-III and E have been associated with risk of arterial thrombotic diseases. We investigated whether these apolipoproteins have prothrombotic properties and are associated with risk of venous thromboembolism (VTE).

Patients And Methods: A total of 127 VTE patients and 299 controls were randomly selected from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study (1999-2004), in the Netherlands. The apolipoproteins were quantified using mass spectrometry (LC/MS/MS), and their levels were analyzed as continuous variable (per SD increase).

Results: In controls, increases in levels of apolipoproteins were associated with increases in levels of vitamin K-dependent factors, factor XI, antithrombin and clot lysis time. Additionally, increasing apolipoproteins C-III and E levels were associated with higher factor VIII and von Willebrand factor levels. Levels of C-reactive protein were not associated with any apolipoprotein. The age- and sex-adjusted odds ratios of apolipoproteins E, C-III, CII and CI to the risk of venous thrombosis were 1.21 (95% CI, 0.98-1.49), 1.19 (95% CI, 0.99-1.44), 1.24 (95% CI, 0.95-1.61) and 1.06 (95% CI, 0.87-1.30) per SD increase, respectively. These odds ratios did not attenuate after adjustments for statin use, estrogen use, BMI, alcohol use, and self-reported diabetes.

Conclusions: Levels of apolipoproteins C-I, C-II, C-III and E are associated with those of several coagulation factors. However, whether these apolipoproteins are also associated with an increased risk of VTE remains to be established.
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http://dx.doi.org/10.2147/CLEP.S196266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659780PMC
July 2019

Apolipoprotein profiling as a personalized approach to the diagnosis and treatment of dyslipidaemia.

Ann Clin Biochem 2019 05 19;56(3):338-356. Epub 2019 Mar 19.

1 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

An elevated low-density lipoprotein cholesterol concentration is a classical risk factor for cardiovascular disease. This has led to pharmacotherapy in patients with atherosclerotic heart disease or high heart disease risk with statins to reduce serum low-density lipoprotein cholesterol. Even in patients in whom the target levels of low-density lipoprotein cholesterol are reached, there remains a significant residual cardiovascular risk; this is due, in part, to a focus on low-density lipoprotein cholesterol alone and neglect of other important aspects of lipoprotein metabolism. A more refined lipoprotein analysis will provide additional information on the accumulation of very low-density lipoproteins, intermediate density lipoproteins, chylomicrons, chylomicron-remnants and Lp(a) concentrations. Instead of measuring the cholesterol and triglyceride content of the lipoproteins, measurement of their apolipoproteins (apos) is more informative. Apos are either specific for a particular lipoprotein or for a group of lipoproteins. In particular measurement of apos in atherogenic particles is more biologically meaningful than the measurement of the cholesterol concentration contained in these particles. Applying apo profiling will not only improve characterization of the lipoprotein abnormality, but will also improve definition of therapeutic targets. Apo profiling aligns with the concept of precision medicine by which an individual patient is not treated as 'average' patient by the average (dose of) therapy. This concept of precision medicine fits the unmet clinical need for stratified cardiovascular medicine. The requirements for clinical application of proteomics, including apo profiling, can now be met using robust mass spectrometry technology which offers desirable analytical performance and standardization.
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http://dx.doi.org/10.1177/0004563219827620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595551PMC
May 2019

Plasma LDL-Cholesterol Level at Admission is Independently Associated with Infarct Size in Patients with ST-Segment Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention.

Cardiol Ther 2019 Jun 13;8(1):55-67. Epub 2019 Feb 13.

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

Introduction: Hypercholesterolemia is a well-known risk factor for developing atherosclerosis and subsequently for the risk of a myocardial infarction (MI). Moreover, it might also be related to the extent of damaged myocardium in the event of a MI. The aim of this study was to evaluate the association of baseline low density lipoprotein-cholesterol (LDL-c) level with infarct size in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneously coronary intervention (pPCI).

Methods: Baseline blood samples were obtained from all patients admitted between 2004 and 2014 with STEMI who underwent pPCI. Patients were excluded in case of out of hospital cardiac arrest, treatment delay of at least 10 h or no complete reperfusion after pPCI in the culprit vessel. Peak creatine kinase (CK) level was used for infarct size estimation, defined as the maximal value during admission.

Results: A total of 2248 patients were included in this study (mean age 61.8 ± 12.2 years; 25.0% female). Mean LDL-c level was 3.6 ± 1.1 mmol/L and median peak CK level was 1275 U/L (IQR 564-2590 U/L). Baseline LDL-c level [β = 0.041; (95% CI 0.019-0.062); p < 0.001] was independently associated with peak CK level. Furthermore, left anterior descending artery as culprit vessel, initial TIMI 0-1 flow in the culprit vessel, male gender, and treatment delay were also correlated with high peak CK level (p < 0.05). Prior aspirin therapy was associated with lower peak CK level [β = - 0.073 (95% CI - 0.146 to 0.000), p = 0.050].

Conclusion: This study demonstrates that besides the more established predictors of infarct size, elevated LDL-c is associated with augmented infarct size in patients with STEMI treated with pPCI.
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http://dx.doi.org/10.1007/s40119-019-0126-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525214PMC
June 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

Apolipoproteins A1, B, and apoB/apoA1 ratio are associated with first ST-segment elevation myocardial infarction but not with recurrent events during long-term follow-up.

Clin Res Cardiol 2019 May 8;108(5):520-538. Epub 2018 Oct 8.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: The current way to assess the risk of cardiovascular disease (CVD) is to measure conventional lipid and lipoprotein cholesterol fractions. Despite the success of statin treatment, residual cardiovascular risk remains high. Therefore, the value of extensive serum apolipoprotein (apo) profiling to assess the risk of ST-segment elevation myocardial infarction (STEMI) and of major adverse cardiac events (MACE) in patients with STEMI was investigated in a case-control design.

Methods And Results: Serum apo levels were measured using liquid chromatography and mass spectrometry in 299 healthy individuals and 220 patients with STEMI. First, the association of apo profiles in baseline samples with risk of STEMI was examined, and second, the association of apo profiles at baseline with risk of recurrent MACE in patients with STEMI in a longitudinal study design was studied. High baseline (> 1.25 g/L) apoA1 levels were associated with a decreased risk of STEMI [odds ratio (OR) 0.17; 95% CI 0.11-0.26], whereas high apoB (> 1.00 g/L) levels (OR 2.17; 95% CI 1.40-3.36) and apoB/apoA1 ratio (OR per 1 SD (OR/SD): 2.16; 95% CI 1.76-2.65) were associated with an increased risk. Very-low-density-lipoprotein (VLDL)-associated apos gave conflicting results. Neither conventional lipid levels nor apo levels were associated with MACE in the STEMI group.

Conclusion: In conclusion, apoA1, apoB, and apoB/apoA1 were strongly associated with risk of STEMI. No clear relation between VLDL-associated apos and the risk of STEMI was found. Neither baseline serum apos nor lipids predicted MACE in statin-treated patients during long-term follow-up after a first STEMI.
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http://dx.doi.org/10.1007/s00392-018-1381-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484771PMC
May 2019

Detecting molecular forms of antithrombin by LC-MRM-MS: defining the measurands.

Clin Chem Lab Med 2018 09;56(10):1704-1714

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1515/cclm-2017-1111DOI Listing
September 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

Robust and Accurate 2-Year Performance of a Quantitative Mass Spectrometry-Based Apolipoprotein Test in a Clinical Chemistry Laboratory.

Clin Chem 2018 04 29;64(4):747-749. Epub 2018 Jan 29.

Department of Clinical Chemistry and Laboratory Medicine Leiden University Medical Center Leiden, the Netherlands

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http://dx.doi.org/10.1373/clinchem.2017.285098DOI Listing
April 2018

RGDfK-Peptide Modified Alginate Scaffold for Cell Transplantation and Cardiac Neovascularization.

Tissue Eng Part A 2018 05 13;24(9-10):740-751. Epub 2017 Nov 13.

1 Department of Surgery, Columbia University Medical Center , New York, New York.

Cell implantation for tissue repair is a promising new therapeutic strategy. Although direct injection of cells into tissue is appealing, cell viability and retention are not very good. Cell engraftment and survival following implantation are dependent on a sufficient supply of oxygen and nutrients through functional microcirculation as well as a suitable local microenvironment for implanted cells. In this study, we describe the development of a porous, biocompatible, three-dimensional (3D) alginate scaffold covalently modified with the synthetic cyclic RGDfK (Arg-Gly-Asp-D-Phe-Lys) peptide. Cyclic RGDfK peptide is protease resistant, highly stable in aqueous solutions, and has high affinity for cellular integrins. Cyclic RGDfK-modified alginate scaffolds were generated using a novel silicone sheet sandwich technique in combination with freeze-gelation, resulting in highly porous nonimmunogenic scaffolds that promoted both human and rodent cell survival in vitro, and neoangiogenesis in vivo. Two months following implantation in abdominal rectus muscles in rats, cyclic RGDfK-modified scaffolds were fully populated by host cells, especially microvasculature without an overt immune response or fibrosis, whereas unmodified control scaffolds did not show cell ingrowth. Importantly, modified scaffolds that were seeded with human mesenchymal precursor cells and were patched to the epicardial surface of infarcted myocardium induced myocardial neoangiogenesis and significantly improved cardiac function. In summary, purified cyclic RGDfK peptide-modified 3D alginate scaffolds are biocompatible and nonimmunogenic, enhance cell viability, promote angiogenesis, and may be used as a means to deliver cells to myocardial infarct areas to improve neovascularization and cardiac function.
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http://dx.doi.org/10.1089/ten.TEA.2017.0221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963542PMC
May 2018

Low levels of apolipoprotein-CII in normotriglyceridemic patients with very premature coronary artery disease: Observations from the MISSION! Intervention study.

J Clin Lipidol 2017 Nov - Dec;11(6):1407-1414. Epub 2017 Aug 8.

Department of Clinical Chemistry & Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Background: While the overall acute myocardial infarction rates declined in women and men, premature acute myocardial infarction rates remained stable in men and increased in women.

Objective: The purpose of this study was to assess whether baseline apolipoprotein (apo) levels, clinical characteristics, and follow-up of patients with very premature coronary artery disease (CAD) could provide novel clues for the identification of high-risk individuals.

Methods: Apos were measured with a validated quantification liquid chromatography-mass spectrometry method in a well-defined cohort of 38 patients aged ≤45 years admitted with acute ST-segment elevation myocardial infarction.

Results: Mean age was 39.8 ± 4.6 years and 24% was female. Four of these patients (11%) had apoCII levels ≤5.0 mg/L. Compared with the very premature CAD group with apoCII > 5 mg/L, the patients with apoCII levels ≤5.0 mg/L were all females, tended to be younger (35.8 ± 8.4 years vs 40.3 ± 3.9 years, P = .063), had more often a family history of cardiovascular disease ≤65 years (P = .034) and a significantly lower Framingham risk score (P = .001). They presented with normal triglyceride levels, and had lower low-density lipoprotein cholesterol, apoB, and apoE levels. Corrected for differences in risk profile, apoCII ≤ 5 mg/L was associated with increased risk of 10-years reinfarction or revascularization (hazard ratio 7.9 [95% confidence interval 1.5-41.6], P = .015).

Conclusions: In 38 patients with very premature CAD, 11% were found to have low apoCII levels (≤5.0 mg/L) with normal triglyceride levels. Despite their low a priori risk for CAD, these patients presented with ST-segment elevation myocardial infarction and had a high relative risk of 10-year reinfarction or revascularization. This particular phenotype of relatively young female patients with CAD is not recognized earlier and deserves further study.
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http://dx.doi.org/10.1016/j.jacl.2017.08.002DOI Listing
July 2018

Optimization of alginate purification using polyvinylidene difluoride membrane filtration: Effects on immunogenicity and biocompatibility of three-dimensional alginate scaffolds.

J Biomater Appl 2016 10 25;31(4):510-520. Epub 2016 Apr 25.

Department of Surgery, Columbia University Medical Center, USA.

Sodium alginate is an effective biomaterial for tissue engineering applications. Non-purified alginate is contaminated with protein, lipopolysaccharide, DNA, and RNA, which could elicit adverse immunological reactions. We developed a purification protocol to generate biocompatible alginate based on (a) activated charcoal treatment, (b) use of hydrophobic membrane filtration (we used hydrophobic polyvinylidene difluoride membranes to remove organic contaminants), (c) dialysis, and finally (d) ethanol precipitation. Using this approach, we could omit pre-treatment with chloroform and significantly reduce the quantities of reagents used. Purification resulted in reduction of residual protein by 70% down to 0.315 mg/g, DNA by 62% down to 1.28 µg/g, and RNA by 61% down to less than 10 µg/g, respectively. Lipopolysaccharide levels were reduced by >90% to less than 125 EU/g. Purified alginate did not induce splenocyte proliferation in vitro. Three-dimensional scaffolds generated from purified alginate did not elicit a significant foreign body reaction, fibrotic overgrowth, or macrophage infiltration 4 weeks after implantation. This study describes a simplified and economical alginate purification method that results in alginate purity, which meets clinically useful criteria.
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http://dx.doi.org/10.1177/0885328216645952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479495PMC
October 2016

Automated Multiplex LC-MS/MS Assay for Quantifying Serum Apolipoproteins A-I, B, C-I, C-II, C-III, and E with Qualitative Apolipoprotein E Phenotyping.

Clin Chem 2016 Jan 19;62(1):188-97. Epub 2015 Nov 19.

Department of Clinical Chemistry and Laboratory Medicine,

Background: Direct and calculated measures of lipoprotein fractions for cardiovascular risk assessment suffer from analytical inaccuracy in certain dyslipidemic and pathological states, most commonly hypertriglyceridemia. LC-MS/MS has proven suitable for multiplexed quantification and phenotyping of apolipoproteins. We developed and provisionally validated an automated assay for quantification of apolipoprotein (apo) A-I, B, C-I, C-II, C-III, and E and simultaneous qualitative assessment of apoE phenotypes.

Methods: We used 5 value-assigned human serum pools for external calibration. Serum proteins were denatured, reduced, and alkylated according to standard mass spectrometry-based proteomics procedures. After trypsin digestion, peptides were analyzed by LC-MS/MS. For each peptide, we measured 2 transitions. We compared LC-MS/MS results to those obtained by an immunoturbidimetric assay or ELISA.

Results: Intraassay CVs were 2.3%-5.5%, and total CVs were 2.5%-5.9%. The LC-MS/MS assay correlated (R = 0.975-0.995) with immunoturbidimetric assays with Conformité Européenne marking for apoA-I, apoB, apoC-II, apoC-III, and apoE in normotriglyceridemic (n = 54) and hypertriglyceridemic (n = 46) sera. Results were interchangeable for apoA-I ≤3.0 g/L (Deming slope 1.014) and for apoB-100 ≤1.8 g/L (Deming slope 1.016) and were traceable to higher-order standards.

Conclusions: The multiplex format provides an opportunity for new diagnostic and pathophysiologic insights into types of dyslipidemia and allows a more personalized approach for diagnosis and treatment of lipid abnormalities.
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http://dx.doi.org/10.1373/clinchem.2015.246702DOI Listing
January 2016

Serum Cardiac Troponin-I is Superior to Troponin-T as a Marker for Left Ventricular Dysfunction in Clinically Stable Patients with End-Stage Renal Disease.

PLoS One 2015 3;10(8):e0134245. Epub 2015 Aug 3.

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

Background: Serum troponin assays, widely used to detect acute cardiac ischemia, might be useful biomarkers to detect chronic cardiovascular disease (CVD). Cardiac-specific troponin-I (cTnI) and troponin-T (cTnT) generally detect myocardial necrosis equally well. In dialysis patients however, serum cTnT levels are often elevated, unlike cTnI levels. The present study aims to elucidate the associations of cTnI and cTnT with CVD in clinically stable dialysis patients.

Methods: Troponin levels were measured using 5th generation hs-cTnT assays (Roche) and STAT hs-cTnI assays (Abbott) in a cohort of dialysis patients. Serum troponin levels were divided into tertiles with the lowest tertile as a reference value. Serum troponins were associated with indicators of CVD such as left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and the presence of coronary artery disease (CAD). Associations were explored using regression analysis.

Results: We included 154 consecutive patients, 68±7 years old, 77% male, 70% hemodialysis. Median serum cTnT was 51ng/L (exceeding the 99th percentile of the healthy population in 98%) and median serum cTnI was 13ng/L (elevated in 20%). A high cTnI (T3) was significantly associated with a higher LVMI (Beta 31.60; p=0.001) and LVEF (Beta -4.78; p=0.005) after adjusting for confounders whereas a high serum cTnT was not. CAD was significantly associated with a high cTnT (OR 4.70 p=0.02) but not with a high cTnI. Unlike cTnI, cTnT was associated with residual renal function (Beta:-0.09; p=0.006).

Conclusion: In the present cohort, serum cTnI levels showed a stronger association with LVMI and LVEF than cTnT. However, cTnT was significantly associated with CAD and residual renal function, unlike cTnI. Therefore, cTnI seems to be superior to cTnT as a marker of left ventricular dysfunction in asymptomatic dialysis patients, while cTnT might be better suited to detect CAD in these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134245PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523186PMC
May 2016

Blood Leukocyte Count on Admission Predicts Cardiovascular Events in Patients with Acute Non-ST Elevation Myocardial Infarction.

Int J Angiol 2015 Jun;24(2):127-32

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

We aim to test the hypothesis that blood leukocyte count adds prognostic information in patients with acute non-ST-elevation myocardial infarction (non-STEMI). A total of 585 patients with acute non-STEMI (thrombolysis in myocardial infarction risk score ≥ 3) were enrolled in this cohort retrospective study. Blood leukocyte count was measured immediately after admission in the emergency department. The composite of death, reinfarction, urgent revascularization, and stroke during hospitalization were defined as the primary end point of the study. The mean age of the patients was 61 ± 9.6 years and most of them were male (79%). Using multivariate Cox regression analysis involving seven variables (history of smoking, hypertension, heart rate > 100 beats/minute, serum creatinine level > 1.5 mg/dL, blood leukocyte count > 11,000/µL, use of β-blocker, and use of angiotensin-converting enzyme inhibitor), leukocyte count > 11,000/µL demonstrated to be a strong predictor of the primary end point (hazard ratio = 3.028; 95% confidence interval = 1.69-5.40, p < 0.001). The high blood leukocyte count on admission is an independent predictor of cardiovascular events in patients with acute non-STEMI.
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http://dx.doi.org/10.1055/s-0035-1544178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452600PMC
June 2015

Stem and progenitor cell therapy for pulmonary arterial hypertension: effects on the right ventricle (2013 Grover Conference Series).

Pulm Circ 2015 Mar;5(1):73-80

Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA.

In experimental animals and in patients with pulmonary arterial hypertension (PAH), a wide spectrum of structural and functional conditions is known that may be responsible for the switch of a state of "compensated" right ventricular (RV) hypertrophy to a state of RV failure. In recent years, therapy with differentiated cells, endothelial progenitor cells, and mesenchymal stem cells has been shown to cause partial or complete reversal of pathological characteristics of PAH. The therapeutic effects of stem or progenitor cell therapy are considered to be (1) paracrine effects from stem or progenitor cells that had engrafted in the myocardium (or elsewhere), by compounds that have anti-inflammatory, antiapoptotic, and proangiogenic actions and (2) unloading effects on the right ventricle due to stem or progenitor cell-induced decrease in pulmonary vascular resistance and decrease in pulmonary artery pressure.
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http://dx.doi.org/10.1086/679701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405720PMC
March 2015

Quantifying protein measurands by peptide measurements: where do errors arise?

J Proteome Res 2015 Feb 6;14(2):928-42. Epub 2015 Jan 6.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center (LUMC) , Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Clinically actionable quantification of protein biomarkers by mass spectrometry (MS) requires analytical performance in concordance with quality specifications for diagnostic tests. Laboratory-developed tests should, therefore, be validated in accordance with EN ISO 15189:2012 guidelines for medical laboratories to demonstrate competence and traceability along the entire workflow, including the selected standardization strategy and the phases before, during, and after proteolysis. In this study, bias and imprecision of a previously developed MS method for quantification of serum apolipoproteins A-I (Apo A-I) and B (Apo B) were thoroughly validated according to Clinical and Laboratory Standards Institute (CLSI) guidelines EP15-A2 and EP09-A3, using 100 patient sera and either stable-isotope labeled (SIL) peptides or SIL-Apo A-I as internal standard. The systematic overview of error components assigned sample preparation before the first 4 h of proteolysis as major source (∼85%) of within-sample imprecision without external calibration. No improvement in imprecision was observed with the use of SIL-Apo A-I instead of SIL-peptides. On the contrary, when the use of SIL-Apo A-I was combined with external calibration, imprecision improved significantly (from ∼9% to ∼6%) as a result of the normalization for matrix effects on linearity. A between-sample validation of bias in 100 patient sera further supported the presence of matrix effects on digestion completeness and additionally demonstrated specimen-specific biases associated with modified peptide sequences or alterations in protease activity. In conclusion, the presented overview of bias and imprecision components contributes to a better understanding of the sources of errors in MS-based protein quantification and provides valuable recommendations to assess and control analytical quality in concordance with the requirements for clinical use.
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http://dx.doi.org/10.1021/pr5011179DOI Listing
February 2015

Impact of Timing of Eptifibatide Administration on Preprocedural Infarct-Related Artery Patency in Acute STEMI Patients Undergoing Primary PCI.

Int J Angiol 2014 Sep;23(3):207-14

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

The appropriate timing of eptifibatide initiation for acute ST segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) remains unclear. This study aimed to analyze the impact of timing of eptifibatide administration on infarct-related artery (IRA) patency in STEMI patients undergoing primary PCI. Acute STEMI patients who underwent primary PCI (n = 324) were enrolled in this retrospective study; 164 patients received eptifibatide bolus ≤ 30 minutes after emergency department (ED) admission (group A) and 160 patients received eptifibatide bolus > 30 minutes after ED admission (group B). The primary endpoint was preprocedural IRA patency. Most patients in group A (90%) and group B (89%) were late presenters (> 2 hours after symptom onset). The two groups had similar preprocedural thrombolysis in myocardial infarction 2 or 3 flow of the IRA (26 vs. 24%, p = not significant [NS]), similar creatine kinase-MB (CK-MB) levels at 8 hours after admission (339 vs. 281 U/L, p = NS), similar left ventricular ejection fraction (LVEF) (52 vs. 50%, p = NS), and similar 30-day mortality (2 vs. 7%, p = NS). Compared with group B, patients in group A had shorter door-to-device time (p < 0.001) and shorter procedural time (p = 0.004), without increased bleeding risk (13 vs. 18%, p = NS). Earlier intravenous administration of eptifibatide before primary PCI did not improve preprocedural IRA patency, CK-MB level at 8 hours after admission, LVEF and 30-day mortality compared with patients who received intravenous eptifibatide that was administered later.
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http://dx.doi.org/10.1055/s-0034-1382158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169102PMC
September 2014

Metrological traceability in mass spectrometry-based targeted protein quantitation: a proof-of-principle study for serum apolipoproteins A-I and B100.

J Proteomics 2014 Sep 25;109:143-61. Epub 2014 Jun 25.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. Electronic address:

Unlabelled: In this study, we have followed up on previous liquid chromatography (LC) multiple reaction monitoring (MRM) mass spectrometry (MS) approaches for measurement of apolipoprotein (apo) A-I and apo B100 in serum aiming for implementation of a multiplexed assay in a clinical chemistry laboratory with full metrological traceability. Signature peptides were selected and detected by dynamic MRM, and stable isotope labeled (SIL)-peptides were used as internal standards. Five apo A-I and four apo B100 peptides were measured in serum digests with linearity (R(2)>0.992) in the physiologically relevant concentration ranges. Linearity with regard to protein concentration was ascertained at five concentration levels (R(2)>0.926 and R(2)>0.965, for the apo A-I and apo B100 peptides, respectively). Three native value-assigned sera were used as external calibrators for further method verification. Imprecision values on sample preparation and LC-MS/MS acquisition were below the established minimal specifications for apo A-I and apo B100 (5.0% and 5.3%, respectively). Correlation of LC-MS/MS results with immunoturbidimetric assay results, for normo- and hypertriglyceridemic samples, showed R(2)>0.944 for apo A-I and R(2)>0.964 for apo B100. This LC-MS/MS method has potential for clinical application in normo- and dyslipidemic patients.

Biological Significance: Measurement of apo A-I and apo B100 may offer an alternative to high and low density lipoprotein cholesterol (HDL-c and LDL-c) methods for cardiovascular disease risk assessment in dyslipidemic patients [1]. An LC-MS/MS method for apo A-I and apo B100 has the advantage of antibody independent and specific detection of protein signature peptides. The introduction of an LC-MS/MS method for apo A-I and apo B100 can serve as an example for many existing and newly developed (multiplex) biomarker methods in quantitative clinical chemistry proteomics (qCCP). Such LC-MS/MS methods should meet basic clinical chemistry principles with regard to test evaluation [2]. Criteria for imprecision should be pre-defined, e.g., based on biological variation. The use of commutable and traceable serum-based calibrators will improve inter-laboratory reproducibility of LC-MS/MS methods and may contribute to a more rapid transition of biomarker discovery to clinical utility with benefit for the patient treatment and improvement of general health care.
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http://dx.doi.org/10.1016/j.jprot.2014.06.015DOI Listing
September 2014

Clinical impact of direct HDLc and LDLc method bias in hypertriglyceridemia. A simulation study of the EAS-EFLM Collaborative Project Group.

Atherosclerosis 2014 Mar 4;233(1):83-90. Epub 2014 Jan 4.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Background: Despite international standardization programs for LDLc and HDLc measurements, results vary significantly with methods from different manufacturers. We aimed to simulate the impact of analytical error and hypertriglyceridemia on HDLc- and LDLc-based cardiovascular risk classification.

Methods: From the Dutch National EQA-2012 external quality assessment of 200 clinical laboratories, we examined data from normotriglyceridemic (∼ 1 mmol/l) and hypertriglyceridemic (∼ 7 mmol/l) serum pools with lipid target values assigned by the Lipid Reference Laboratory in Rotterdam. HDLc and LDLc were measured using direct methods of Abbott, Beckman, Siemens, Roche, Olympus, or Ortho Clinical Diagnostics. We simulated risk reclassification using HDL- and sex-specific SCORE multipliers considering two fictitious moderate-risk patients with initial SCORE 4% (man) and 3% (woman). Classification into high-risk treatment groups (LDLc >2.50 mmol/l) was compared between calculated LDLc and direct LDLc methods.

Results: Overall HDLc measurements in hypertriglyceridemic serum showed negative mean bias of -15%. HDL-multipliers falsely reclassified 70% of women and 43% of men to a high-risk (SCORE >5%) in hypertriglyceridemic serum (P < 0.0001 vs. normotriglyceridemic serum) with method-dependent risk reclassifications. Direct LDLc in hypertriglyceridemic serum showed positive mean bias with Abbott (+16%) and Beckman (+14%) and negative mean bias with Roche (-7%). In hypertriglyceridemic serum, 57% of direct LDLc measurements were above high-risk treatment goal (2.50 mmol/l) vs. 29% of direct LDLc (33% of calculated LDLc) in normotriglyceridemic sera.

Conclusion: LDLc and HDLc measurements are unreliable in severe hypertriglyceridemia, and should be applied with caution in SCORE risk classification and therapeutic strategies.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.016DOI Listing
March 2014

Temporal trends of system of care for STEMI: insights from the Jakarta Cardiovascular Care Unit Network System.

PLoS One 2014 10;9(2):e86665. Epub 2014 Feb 10.

Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands ; Interuniversity Cardiology Institute the Netherlands, Utrecht, the Netherlands.

Aim: Guideline implementation programs are of paramount importance in optimizing acute ST-elevation myocardial infarction (STEMI) care. Assessment of performance indicators from a local STEMI network will provide knowledge of how to improve the system of care.

Methods And Results: Between 2008-2011, 1505 STEMI patients were enrolled. We compared the performance indicators before (n = 869) and after implementation (n = 636) of a local STEMI network. In 2011 (after introduction of STEMI networking) compared to 2008-2010, there were more inter-hospital referrals for STEMI patients (61% vs 56%, p<0.001), more primary percutaneous coronary intervention (PCI) procedures (83% vs 73%, p = 0.005), and more patients reaching door-to-needle time ≤ 30 minutes (84.5% vs 80.2%, p<0.001). However, numbers of patients who presented very late (>12 hours after symptom onset) were similar (53% vs 51%, NS). Moreover, the numbers of patients with door-to-balloon time ≤ 90 minutes were similar (49.1% vs 51.3%, NS), and in-hospital mortality rates were similar (8.3% vs 6.9%, NS) in 2011 compared to 2008-2010.

Conclusion: After a local network implementation for patients with STEMI, there were significantly more inter-hospital referral cases, primary PCI procedures, and patients with a door-to-needle time ≤ 30 minutes, compared to the period before implementation of this network. However, numbers of patients who presented very late, the targeted door-to-balloon time and in-hospital mortality rate were similar in both periods. To improve STEMI networking based on recent guidelines, existing pre-hospital and in-hospital protocols should be improved and managed more carefully, and should be accommodated whenever possible.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919720PMC
October 2014

Confounding factors in the relation between high sensitivity cardiac troponin T levels in serum and infarct size of patients with first ST-elevation myocardial infarction.

Int J Cardiol 2014 Mar 4;172(1):e3-5. Epub 2014 Jan 4.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1016/j.ijcard.2013.12.141DOI Listing
March 2014

Evaluation of interspecimen trypsin digestion efficiency prior to multiple reaction monitoring-based absolute protein quantification with native protein calibrators.

J Proteome Res 2013 Dec 13;12(12):5760-74. Epub 2013 Nov 13.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center (LUMC) , Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.

Implementation of quantitative clinical chemistry proteomics (qCCP) requires targeted proteomics approaches, usually involving bottom-up multiple reaction monitoring-mass spectrometry (MRM-MS) with stable-isotope labeled standard (SIS) peptides, to move toward more accurate measurements. Two aspects of qCCP that deserve special attention are (1) proper calibration and (2) the assurance of consistent digestion. Here, we describe the evaluation of tryptic digestion efficiency by monitoring various signature peptides, missed cleavages, and modifications during proteolysis of apolipoprotein A-I and B in normo- and hypertriglyceridemic specimens. Absolute quantification of apolipoprotein A-I and B was performed by LC-MRM-MS with SIS peptide internal standards at two time points (4 and 20 h), using three native protein calibrators. Comparison with an immunoturbidimetric assay revealed recoveries of 99.4 ± 6.5% for apolipoprotein A-I and 102.6 ± 7.2% for apolipoprotein B after 4 h of trypsin digestion. Protein recoveries after 20 h trypsin incubation equaled 95.9 ± 6.9% and 106.0 ± 10.0% for apolipoproteins A-I and B, respectively. In conclusion, the use of metrologically traceable, native protein calibrators looks promising for accurate quantification of apolipoprotein A-I and B. Selection of rapidly formed peptides, that is, with no or minor missed cleavages, and the use of short trypsin incubation times for these efficiently cleaved peptides are likely to further reduce the variability introduced by trypsin digestion and to improve the traceability of test results to reach the desirable analytical performance for clinical chemistry application.
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http://dx.doi.org/10.1021/pr400763dDOI Listing
December 2013

Exercise-resembling effects of periodic somatosensory stimulation in heart failure.

Int J Cardiol 2013 Oct 3;168(4):3327-33. Epub 2013 May 3.

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health, Academic Medical Centre, Amsterdam, The Netherlands.

Background: The mechanism of the beneficial effects of exercise training on autonomic derangement and neurohumoral activation in chronic heart failure (CHF) is largely unexplained. In our here-presented hypothesis-generating study we propose that part of these effects is mediated by the exercise-accompanying somatosensory nerve traffic. To demonstrate this, we compared the effects of periodic electrical somatosensory stimulation in patients with CHF with the effects of exercise training and with usual care.

Methods: In a randomized controlled study we measured, in CHF patients, changes in blood pressure, baroreflex sensitivity (BRS), neurohormones, exercise capacity and quality of life (QOL) in response to periodic somatosensory stimulation in the form of 2 Hz transcutaneous electrical nerve stimulation (TENS) at both feet, in response to conventional exercise training (EXTR) and, as control (CTRL), in patients with usual care only.

Results: Group sizes were N=31 (TENS group), N=25 (EXTR group) and N=30 (CTRL group), respectively. Practically all improvements in BRS, neurohormone concentrations, exercise capacity and QOL in the TENS group were comparable to, or sometimes even better than in the EXTR group. These improvements were not observed in the CTRL group.

Conclusions: This study demonstrates that periodic electrical somatosensory stimulation is as effective as exercise training in improving BRS, neurohormone concentrations, exercise capacity and QOL in CHF patients. These results encourage exploration of exercise modalities that concentrate on rhythm rather than on effort, with the purpose to normalize autonomic derangement and neurohumoral activation in CHF.
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http://dx.doi.org/10.1016/j.ijcard.2013.04.040DOI Listing
October 2013

Will future troponin measurement overrule the ECG as the primary diagnostic tool in patients with acute coronary syndrome?

J Electrocardiol 2013 Jul-Aug;46(4):312-7. Epub 2013 Mar 13.

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

To improve patient outcome, point-of-care (POC) cardiac troponin I/T (cTn I/T) tests applied in a prehospital setting and/or emergency department might play a role as a substitute for central hospital laboratory high-sensitivity (hs) cTn I/T testing if their analytical and clinical performance are equivalent to central hospital laboratory hs cTn I/T tests and if they fulfill an unmet clinical need in the diagnostic work-up of patients with acute coronary syndrome (ACS). To date, current point-of-care (POC) cTn I/T tests are not yet sufficiently analytically sensitive and do not provide accurate and precise values in the reference range nor at the 99th percentile of a healthy reference population. Awaiting the development of improved hs POC cTn I/T tests, current POC cTn I/T tests should be combined with ECG as it takes several hours to detect a rise of cTn I/T in the circulation whereas ischemia-induced ECG changes may be observed soon after onset of chest pain. Although patients with acute ST-segment elevation myocardial infarction (STEMI) are generally diagnosed by ischemic symptoms and ECG only, hospitalized patients with non-STEMI and unstable angina pectoris (UAP) should preferentially be tested with ECG and central hospital laboratory hs cTn I/T tests unless the ECG has already demonstrated diagnostic changes. More evidence and future trials are needed to find out whether in patients with NSTE ACS hs cTn I/T tests should be combined with other tests, such as a test of B-type natriuretic peptide or NT-proBNP.
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http://dx.doi.org/10.1016/j.jelectrocard.2013.02.007DOI Listing
January 2014

Peak and fixed-time high-sensitive troponin for prediction of infarct size, impaired left ventricular function, and adverse outcomes in patients with first ST-segment elevation myocardial infarction receiving percutaneous coronary intervention.

Am J Cardiol 2013 May 24;111(10):1387-93. Epub 2013 Apr 24.

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

The clinical use of advanced imaging modalities for early determination of infarct size and prognosis is limited. As a specific indicator of myocardial necrosis, cardiac troponin T (cTnT) can be used as a surrogate measure for this purpose. The present study sought to investigate the use of peak and serial 6-hour fixed-time high-sensitive (hs) cTnT for estimation of infarct size, left ventricular (LV) function, and prognosis in consecutive patients with ST-segment elevation myocardial infarction. The infarct size was expressed as the 48-hour cumulative creatine kinase release. LV function at 3 months was assessed using the echocardiographic wall motion score index and LV ejection fraction using radionuclide ventriculography. Adverse outcomes, comprising all-cause death, implantable cardioverter-defibrillator implantation, or hospitalization for heart failure, were recorded at 1 year of follow-up. In 188 patients, the peak and all fixed-time values correlated significantly with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction. The hs-cTnT value at 24 hours demonstrated the greatest correlation (r = 0.86, r = 0.47, and r = -0.59, respectively; p <0.001 for all). In the multivariate regression models adjusted for the clinical parameters, almost all were independently associated with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction, with the hs-cTnT value at 24 hours having the largest effect. Moreover, all cTnT values independently predicted adverse outcomes, again, with the hs-cTnT value at 24 hours showing the largest influence (hazard ratio 3.77, 95% confidence interval 2.12 to 6.73, p <0.001). In conclusion, not only peak, but all fixed-time hs-cTnT values were associated with infarct size, LV function at 3 months, and adverse outcomes 1 year after ST-segment elevation myocardial infarction. The value 24 hours after the onset of symptoms had the closest associations with all outcomes. Therefore, serial sampling for a peak value might be redundant.
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http://dx.doi.org/10.1016/j.amjcard.2013.01.284DOI Listing
May 2013

Depolarization-induced automaticity in rat ventricular cardiomyocytes is based on the gating properties of L-type calcium and slow Kv channels.

Eur Biophys J 2013 Apr 23;42(4):241-55. Epub 2012 Oct 23.

Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.

Depolarization-induced automaticity (DIA) of cardiomyocytes is the property of those cells to generate pacemaker cell-like spontaneous electrical activity when subjected to a depolarizing current. This property provides a candidate mechanism for generation of pathogenic ectopy in cardiac tissue. The purpose of this study was to determine the biophysical mechanism of DIA in terms of the ion conductance properties of the cardiomyocyte membrane. First, we determined, by use of the conventional whole-cell patch-clamp technique, the membrane conductance and DIA properties of ventricular cardiomyocytes isolated from adult rat heart. Second, we reproduced and analysed DIA properties by using an adapted version of the experimentally based mathematical cardiomyocyte model of Pandit et al. (Biophys J 81:3029-3051 2001, Biophys J 84:832-841 2003) and Padmala and Demir (J Cardiovasc Electrophysiol 14:990-995 2003). DIA in 23 rat cardiomyocytes was a damped membrane potential oscillation with a variable number of action potentials and/or waves, depending on the strength of the depolarizing current and the particular cell. The adapted model was used to reconstruct the DIA properties of a particular cardiomyocyte from its whole-cell voltage-clamp currents. The main currents involved in DIA were an L-type calcium current (I CaL) and a slowly activating and inactivating Kv current (I ss), with linear (I B) and inward rectifier (I K1) currents acting as background currents and I Na and I t as modulators. Essential for DIA is a sufficiently large window current of a slowly inactivating I CaL combined with a critically sized repolarizing current I ss. Slow inactivation of I ss makes DIA transient. In conclusion, we established a membrane mechanism of DIA primarily based on I CaL, I ss and inward rectifier properties; this may be helpful in understanding cardiac ectopy and its treatment.
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http://dx.doi.org/10.1007/s00249-012-0866-9DOI Listing
April 2013

Pre-infarction angina predicts thrombus burden in patients admitted for ST-segment elevation myocardial infarction.

EuroIntervention 2012 Apr;7(12):1396-405

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

Aims: In patients with ST-elevation myocardial infarction (STEMI), high thrombotic burden, subsequent distal embolisation and myocardial no-reflow remain a large obstacle that may negate the benefits of urgent coronary revascularisation. We aimed at assessing the predictors of: 1) thrombus grade in patients undergoing primary percutaneous coronary intervention (PPCI) and 2) infarct size, in order to optimise therapy to reduce thrombus burden.

Methods And Results: One-hundred and fifty-three consecutive patients presenting with STEMI and undergoing PPCI were included. Thrombus was evaluated by angiography and scored according to the TIMI study group score. Next, patients were categorised into two groups that had either high thrombus grade (HTG; score 4-5) or low thrombus grade (LTG; score 1-3). We evaluated predictors of angiographic thrombus grade among a number of clinical, angiographic and laboratory data. We also assessed infarct size and scintigraphic left ventricular ejection fraction (LVEF) at three months in both patient groups. Ninety-four patients (58±11 years; 75% males) presented with HTG, whereas 59 patients (58±12 years; 78% males) presented with LTG. Pre-infarction angina (PIA) was more frequently encountered in the LTG group than in the HTG group (25% vs. 10%, p=0.009). Pre-procedural TIMI flow was significantly lower in the HTG group (p<0.001), and thrombosuction was more frequently applied in the HTG group (p<0.001). Absence of PIA (OR=0.29, 95% CI=0.11-0.75, p=0.01) and proximal culprit lesion (OR=2.10, 95% CI=1.02-4.36, p=0.04) were the only independent predictors of HTG. HTG proved an independent predictor of higher peak levels of creatine kinase (CK) (p<0.001) and troponin T (p<0.001), as well as lower LVEF (p=0.05) along with male gender and absence of prior statin therapy.

Conclusions: Absence of PIA and proximal culprit lesions are associated with higher thrombus grade. Higher thrombus grade is associated with larger infarct size and slightly worse LV function. This may have clinical implications in planning strategies, particularly regarding pharmacotherapy, that aim to decrease thrombus burden prior to stent implantation.
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http://dx.doi.org/10.4244/EIJV7I12A219DOI Listing
April 2012

Spontaneous ventricular fibrillation in right ventricular failure secondary to chronic pulmonary hypertension.

Circ Arrhythm Electrophysiol 2012 Feb 22;5(1):181-90. Epub 2011 Dec 22.

Department of Anesthesiology, UCLA School of Medicine, BH-160CHS, 650 Charles Young Dr, Los Angeles, CA 90095-7115, USA.

Background: Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. We test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality.

Methods And Results: Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (control, n=17). Activation pattern of the RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day 21 and progressed to RVF by approximately day 30. Rats manifested increased mortality, and ≈30% rats died suddenly and precipitously during 23-32 days after MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV, which was subsequently maintained by both focal and incomplete reentrant wave fronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization-mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23±8 ms. The RV but not the left ventricular cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion, and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the control hearts. RVF was associated with significantly reduced RV ejection fraction (P<0.001), RV hypertrophy (P<0.001), and RV fibrosis (P<0.01). The hemodynamic function of the LV and its structure were preserved.

Conclusions: PH-induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an early afterdepolarization-mediated triggered activity.
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http://dx.doi.org/10.1161/CIRCEP.111.967265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319685PMC
February 2012

Connexin43 silencing in myofibroblasts prevents arrhythmias in myocardial cultures: role of maximal diastolic potential.

Cardiovasc Res 2012 Mar 22;93(3):434-44. Epub 2011 Dec 22.

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

Aims: Arrhythmogenesis in cardiac fibrosis remains incompletely understood. Therefore, this study aims to investigate how heterocellular coupling between cardiomyocytes (CMCs) and myofibroblasts (MFBs) affects arrhythmogeneity of fibrotic myocardial cultures. Potentially, this may lead to the identification of novel anti-arrhythmic strategies.

Methods And Results: Co-cultures of neonatal rat CMCs and MFBs in a 1:1 ratio were used as a model of cardiac fibrosis, with purified CMC cultures as control. Arrhythmogeneity was studied at day 9 of culture by voltage-sensitive dye mapping. Heterocellular coupling was reduced by transducing MFBs with lentiviral vectors encoding shRNA targeting connexin43 (Cx43) or luciferase (pLuc) as control. In fibrotic cultures, conduction velocity (CV) was lowered (11.2 ± 1.6 cm/s vs. 23.9 ± 2.1 cm/s; P < 0.0001), while action potential duration and ectopic activity were increased. Maximal diastolic membrane potential (MDP) of CMCs was less negative in fibrotic cultures. In fibrotic cultures, (n = 30) 30.0% showed spontaneous re-entrant tachyarrhythmias compared with 5% in controls (n = 60). Cx43 silencing in MFBs made the MDP in CMCs more negative, increased excitability and CV by 51% (P < 0.001), and reduced action potential duration and ectopic activity (P < 0.01), thereby reducing re-entry incidence by 40% compared with pLuc-silenced controls. Anti-arrhythmic effects of Cx43 down-regulation in MFBs was reversed by depolarization of CMCs through I(k1) inhibition or increasing extracellular [K(+)].

Conclusion: Arrhythmogeneity of fibrotic myocardial cultures is mediated by Cx43 expression in MFBs. Reduced expression of Cx43 causes a more negative MDP of CMCs. This preserves CMC excitability, limits prolongation of repolarization and thereby strongly reduces the incidence of spontaneous re-entrant tachyarrhythmias.
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http://dx.doi.org/10.1093/cvr/cvr351DOI Listing
March 2012
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