Publications by authors named "Pieter A Doevendans"

491 Publications

Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias.

J Pers Med 2021 Jun 3;11(6). Epub 2021 Jun 3.

Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset.
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http://dx.doi.org/10.3390/jpm11060502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226909PMC
June 2021

A Roadmap to Cardiac Tissue-Engineered Construct Preservation: Insights from Cells, Tissues, and Organs.

Adv Mater 2021 Jul 28;33(27):e2008517. Epub 2021 May 28.

Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.

Worldwide, over 26 million patients suffer from heart failure (HF). One strategy aspiring to prevent or even to reverse HF is based on the transplantation of cardiac tissue-engineered (cTE) constructs. These patient-specific constructs aim to closely resemble the native myocardium and, upon implantation on the diseased tissue, support and restore cardiac function, thereby preventing the development of HF. However, cTE constructs off-the-shelf availability in the clinical arena critically depends on the development of efficient preservation methodologies. Short- and long-term preservation of cTE constructs would enable transportation and direct availability. Herein, currently available methods, from normothermic- to hypothermic- to cryopreservation, for the preservation of cardiomyocytes, whole-heart, and regenerative materials are reviewed. A theoretical foundation and recommendations for future research on developing cTE construct specific preservation methods are provided. Current research suggests that vitrification can be a promising procedure to ensure long-term cryopreservation of cTE constructs, despite the need of high doses of cytotoxic cryoprotective agents. Instead, short-term cTE construct preservation can be achieved at normothermic or hypothermic temperatures by administration of protective additives. With further tuning of these promising methods, it is anticipated that cTE construct therapy can be brought one step closer to the patient.
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http://dx.doi.org/10.1002/adma.202008517DOI Listing
July 2021

miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a.

Front Cardiovasc Med 2021 19;8:592362. Epub 2021 Mar 19.

Experimental Cardiology Laboratory, Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.

Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3'-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients.
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http://dx.doi.org/10.3389/fcvm.2021.592362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017124PMC
March 2021

Preclinical Feasibility and Patency Analyses of a New Distal Coronary Connector: The ELANA Heart Bypass.

Innovations (Phila) 2021 Mar-Apr;16(2):163-168. Epub 2021 Mar 7.

8124 Department of Cardiothoracic Surgery, University Medical Center Utrecht, The Netherlands.

Objective: This preclinical study determines the feasibility and 6-month patency rates of a new distal coronary connector, the Excimer Laser Assisted Nonocclusive Anastomosis (ELANA) Heart Bypass.

Methods: Twenty Dutch Landrace pigs received either a hand-sewn ( = 8) or an ELANA ( = 12) left internal thoracic artery to left anterior descending artery anastomosis, using off-pump coronary artery bypass grafting. Six-month patency rates were demonstrated by coronary angiography and histological evaluation. Throughout, procedural details and complication rates were collected.

Results: The ELANA Heart Bypass demonstrated 0% mortality and complication rates during follow-up. It was demonstrated feasible, with comparable perioperative flow measurements (ELANA vs hand-sewn, median [min to max], 24 [14 to 28] vs 17 [12 to 31] mL/min; = 0.601) and fast construction times (3 [3 to 7] vs 31 [26 to 37] min; < 0.001). Yet, an extra hemostatic stitch was needed in 25% of the ELANA versus 12.5% of the hand-sewn anastomoses. The 6-month patency rate of the ELANA Heart Bypass was 83.3% versus 100% in hand-sewn anastomoses. The 2 occluded ELANA-anastomoses were defined model-based errors.

Conclusions: The ELANA Heart Bypass facilitates a sutureless distal coronary anastomosis. A design change is suggested to improve hemostasis and will be evaluated in future translational studies. This new technique is a potential alternative to hand-sewn anastomoses in (minimally invasive) coronary surgery.
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http://dx.doi.org/10.1177/1556984521991519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108114PMC
March 2021

Clinical Course Long After Atrial Switch: A Novel Risk Score for Major Clinical Events.

J Am Heart Assoc 2021 Feb 22;10(5):e018565. Epub 2021 Feb 22.

Department of Clinical and Experimental Cardiology Heart Center Amsterdam Cardiovascular SciencesAmsterdam University Medical CenterUniversity of Amsterdam the Netherlands.

Background Patients with transposition of the great arteries corrected by an atrial switch operation experience major clinical events during adulthood, mainly heart failure (HF) and arrhythmias, but data on the emerging risks remain scarce. We assessed the risk for events during the clinical course in adulthood, and provided a novel risk score for event-free survival. Methods and Results This multicenter study observed 167 patients with transposition of the great arteries corrected by an atrial switch operation (61% Mustard procedure; age, 28 [interquartile range, 24-36] years) for 13 (interquartile range, 9-16) years, during which 16 (10%) patients died, 33 (20%) had HF events, defined as HF hospitalizations, heart transplantation, ventricular assist device implantation, or HF-related death, and 15 (9%) had symptomatic ventricular arrhythmias. Five-year risk of mortality, first HF event, and first ventricular arrhythmia increased from 1% each at age 25 years, to 6% (95% CI, 4%-9%), 23% (95% CI, 17%-28%), and 5% (95% CI, 2%-8%), respectively, at age 50 years. Predictors for event-free survival were examined to construct a prediction model using bootstrapping techniques. A prediction model combining age >30 years, prior ventricular arrhythmia, age >1 year at repair, moderate or greater right ventricular dysfunction, severe tricuspid regurgitation, and mild or greater left ventricular dysfunction discriminated well between patients at low (<5%), intermediate (5%-20%), and high (>20%) 5-year risk (optimism-corrected C-statistic, 0.86 [95% CI, 0.82-0.90]). Observed 5- and 10-year event-free survival rates in low-risk patients were 100% and 97%, respectively, compared with only 31% and 8%, respectively, in high-risk patients. Conclusions The clinical course of patients undergoing atrial switch increasingly consists of major clinical events, especially HF. A novel risk score stratifying patients as low, intermediate, and high risk for event-free survival provides information on absolute individual risks, which may support decisions for pharmacological and interventional management.
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http://dx.doi.org/10.1161/JAHA.120.018565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174274PMC
February 2021

Massive expansion and cryopreservation of functional human induced pluripotent stem cell-derived cardiomyocytes.

STAR Protoc 2021 Mar 9;2(1):100334. Epub 2021 Feb 9.

Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.

Since the discovery of human induced pluripotent stem cells (hiPSCs), numerous strategies have been established to efficiently derive cardiomyocytes from hiPSCs (hiPSC-CMs). Here, we describe a cost-effective strategy for the subsequent massive expansion (>250-fold) of high-purity hiPSC-CMs relying on two aspects: removal of cell-cell contacts and small-molecule inhibition with CHIR99021. The protocol maintains CM functionality, allows cryopreservation, and the cells can be used in downstream assays such as disease modeling, drug and toxicity screening, and cell therapy. For complete details on the use and execution of this protocol, please refer to Buikema (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881265PMC
March 2021

Acute recoordination rather than functional hemodynamic improvement determines reverse remodelling by cardiac resynchronisation therapy.

Int J Cardiovasc Imaging 2021 Jun 5;37(6):1903-1911. Epub 2021 Feb 5.

University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands.

Purpose: Cardiac resynchronisation therapy (CRT) improves left ventricular (LV) function acutely, with further improvements and reverse remodelling during chronic CRT. The current study investigated the relation between acute improvement of LV systolic function, acute mechanical recoordination, and long-term reverse remodelling after CRT.

Methods: In 35 patients, LV speckle tracking longitudinal strain, LV volumes & ejection fraction (LVEF) were assessed by echocardiography before, acutely within three days, and 6 months after CRT. A subgroup of 25 patients underwent invasive assessment of the maximal rate of LV pressure rise (dP/dt) during CRT-implantation. The acute change in dP/dt, LVEF, systolic discoordination (internal stretch fraction [ISF] and LV systolic rebound stretch [SRSlv]) and systolic dyssynchrony (standard deviation of peak strain times [2DS-SD18]) was studied, and their association with long-term reverse remodelling were determined.

Results: CRT induced acute and ongoing recoordination (ISF from 45 ± 18 to 27 ± 11 and 23 ± 12%, p < 0.001; SRS from 2.27 ± 1.33 to 0.74 ± 0.50 and 0.71 ± 0.43%, p < 0.001) and improved LV function (dP/dt 668 ± 185 vs. 817 ± 198 mmHg/s, p < 0.001; stroke volume 46 ± 15 vs. 54 ± 20 and 52 ± 16 ml; LVEF 19 ± 7 vs. 23 ± 8 and 27 ± 10%, p < 0.001). Acute recoordination related to reverse remodelling (r = 0.601 and r = 0.765 for ISF & SRSlv, respectively, p < 0.001). Acute functional improvements of LV systolic function however, neither related to reverse remodelling nor to the extent of acute recoordination.

Conclusion: Long-term reverse remodelling after CRT is likely determined by (acute) recoordination rather than by acute hemodynamic improvements. Discoordination may therefore be a more important CRT-substrate that can be assessed and, acutely restored.
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http://dx.doi.org/10.1007/s10554-021-02174-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255256PMC
June 2021

Advanced Modeling to Study the Paradox of Mechanically Induced Cardiac Fibrosis.

Tissue Eng Part C Methods 2021 02;27(2):100-114

Division of Heart and Lungs, Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.

In heart failure, cardiac fibrosis is the result of an adverse remodeling process. Collagen is continuously synthesized in the myocardium in an ongoing attempt of the heart to repair itself. The resulting collagen depositions act counterproductively, causing diastolic dysfunction and disturbing electrical conduction. Efforts to treat cardiac fibrosis specifically have not been successful and the molecular etiology is only partially understood. The differentiation of quiescent cardiac fibroblasts to extracellular matrix-depositing myofibroblasts is a hallmark of cardiac fibrosis and a key aspect of the adverse remodeling process. This conversion is induced by a complex interplay of biochemical signals and mechanical stimuli. Tissue-engineered 3D models to study cardiac fibroblast behavior indicate that cyclic strain can activate a myofibroblast phenotype. This raises the question how fibroblast quiescence is maintained in the healthy myocardium, despite continuous stimulation of ultimately profibrotic mechanotransductive pathways. In this review, we will discuss the convergence of biochemical and mechanical differentiation signals of myofibroblasts, and hypothesize how these affect this paradoxical quiescence. Impact statement Mechanotransduction pathways of cardiac fibroblasts seem to ultimately be profibrotic in nature, but in healthy human myocardium, cardiac fibroblasts remain quiescent, despite continuous mechanical stimulation. We propose three hypotheses that could explain this paradoxical state of affairs. Furthermore, we provide suggestions for future research, which should lead to a better understanding of fibroblast quiescence and activation, and ultimately to new strategies for the prevention and treatment of cardiac fibrosis and heart failure.
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http://dx.doi.org/10.1089/ten.TEC.2020.0298DOI Listing
February 2021

Discovering and Visualizing Disease-Specific Electrocardiogram Features Using Deep Learning: Proof-of-Concept in Phospholamban Gene Mutation Carriers.

Circ Arrhythm Electrophysiol 2021 02 5;14(2):e009056. Epub 2021 Jan 5.

Department of Cardiology, University Medical Center Utrecht, the Netherlands (R.R.v.d.L., K.T., M.N.B., J.F.v.d.H., M.J.C., R.J.H., P.v.d.H., P.A.D., F.W.A., R.v.E.).

Background: ECG interpretation requires expertise and is mostly based on physician recognition of specific patterns, which may be challenging in rare cardiac diseases. Deep neural networks (DNNs) can discover complex features in ECGs and may facilitate the detection of novel features which possibly play a pathophysiological role in relatively unknown diseases. Using a cohort of PLN (phospholamban) p.Arg14del mutation carriers, we aimed to investigate whether a novel DNN-based approach can identify established ECG features, but moreover, we aimed to expand our knowledge on novel ECG features in these patients.

Methods: A DNN was developed on 12-lead median beat ECGs of 69 patients and 1380 matched controls and independently evaluated on 17 patients and 340 controls. Differentiating features were visualized using Guided Gradient Class Activation Mapping++. Novel ECG features were tested for their diagnostic value by adding them to a logistic regression model including established ECG features.

Results: The DNN showed excellent discriminatory performance with a c-statistic of 0.95 (95% CI, 0.91-0.99) and sensitivity and specificity of 0.82 and 0.93, respectively. Visualizations revealed established ECG features (low QRS voltages and T-wave inversions), specified these features (eg, R- and T-wave attenuation in V2/V3) and identified novel PLN-specific ECG features (eg, increased PR-duration). The logistic regression baseline model improved significantly when augmented with the identified features (<0.001).

Conclusions: A DNN-based feature detection approach was able to discover and visualize disease-specific ECG features in PLN mutation carriers and revealed yet unidentified features. This novel approach may help advance diagnostic capabilities in daily practice.
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http://dx.doi.org/10.1161/CIRCEP.120.009056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892204PMC
February 2021

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.

Front Immunol 2020 8;11:599511. Epub 2020 Dec 8.

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

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient's circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.
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http://dx.doi.org/10.3389/fimmu.2020.599511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752942PMC
June 2021

Minimally Invasive Ways of Determining Circadian Rhythms in Humans.

Physiology (Bethesda) 2021 01;36(1):7-20

Department of Cardiology, Experimental Cardiology Laboratory, Division of Heart and Lungs, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands.

Circadian rhythm exerts a critical role in mammalian health and disease. A malfunctioning circadian clock can be a consequence, as well as the cause of several pathophysiologies. Clinical therapies and research may also be influenced by the clock. Since the most suitable manner of revealing this rhythm in humans is not yet established, we discuss existing methods and seek to determine the most feasible ones.
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http://dx.doi.org/10.1152/physiol.00018.2020DOI Listing
January 2021

Efficacy of multi-electrode linear irreversible electroporation.

Europace 2021 Mar;23(3):464-468

Department of Cardiology, Isala Hospital, Heart Centre, Dr Van Heesweg 2, 8025 AB Zwolle, The Netherlands.

Aims: We investigated the efficacy of linear multi-electrode irreversible electroporation (IRE) ablation in a porcine model.

Methods And Results: The study was performed in six pigs (weight 60-75 kg). After median sternotomy and opening of the pericardium, a pericardial cradle was formed and filled with blood. A linear seven polar 7-Fr electrode catheter with 2.5 mm electrodes and 2.5 mm inter-electrode spacing was placed in good contact with epicardial tissue. A single IRE application was delivered using 50 J at one site and 100 J at two other sites, in random sequence, using a standard monophasic defibrillator connected to all seven electrodes connected in parallel. The pericardium and thorax were closed and after 3 weeks survival animals were euthanized. A total of 82 histological sections from all 18 electroporation lesions were analysed. A total of seven 50 J and fourteen 100 J epicardial IRE applications were performed. Mean peak voltages at 50 and 100 J were 1079.2 V ± 81.1 and 1609.5 V ± 56.8, with a mean peak current of 15.4 A ± 2.3 and 20.2 A ± 1.7, respectively. Median depth of the 50 and 100 J lesions were 3.2 mm [interquartile range (IQR) 3.1-3.6] and 5.5 mm (IQR 4.6-6.6) (P < 0.001), respectively. Median lesion width of the 50 and 100 J lesions was 3.9 mm (IQR 3.7-4.8) and 5.4 mm (IQR 5.0-6.3), respectively (P < 0.001). Longitudinal sections showed continuous lesions for 100 J applications.

Conclusion: Epicardial multi-electrode linear application of IRE pulses is effective in creating continuous deep lesions.
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http://dx.doi.org/10.1093/europace/euaa280DOI Listing
March 2021

In vivo analysis of the origin and characteristics of gaseous microemboli during catheter-mediated irreversible electroporation.

Europace 2021 01;23(1):139-146

Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Aims: Irreversible electroporation (IRE) ablation is a non-thermal ablation method based on the application of direct current between a multi-electrode catheter and skin electrode. The delivery of current through blood leads to electrolysis. Some studies suggest that gaseous (micro)emboli might be associated with myocardial damage and/or (a)symptomatic cerebral ischaemic events. The aim of this study was to compare the amount of gas generated during IRE ablation and during radiofrequency (RF) ablation.

Methods And Results: In six 60-75 kg pigs, an extracorporeal femoral shunt was outfitted with a bubble-counter to detect the size and total volume of gas bubbles. Anodal and cathodal 200 J IRE applications were delivered in the left atrium (LA) using a 14-electrode circular catheter. The 30 and 60 s 40 W RF point-by-point ablations were performed. Using transoesophageal echocardiography (TOE), gas formation was visualized. Average gas volumes were 0.6 ± 0.6 and 56.9 ± 19.1 μL (P < 0.01) for each anodal and cathodal IRE application, respectively. Also, qualitative TOE imaging showed significantly less LA bubble contrast with anodal than with cathodal applications. Radiofrequency ablations produced 1.7 ± 2.9 and 6.7 ± 7.4 μL of gas, for 30 and 60 s ablation time, respectively.

Conclusion: Anodal IRE applications result in significantly less gas formation than both cathodal IRE applications and RF applications. This finding is supported by TOE observations.
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http://dx.doi.org/10.1093/europace/euaa243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842095PMC
January 2021

Early- and late anthracycline-induced cardiac dysfunction: echocardiographic characterization and response to heart failure therapy.

Cardiooncology 2020 13;6:23. Epub 2020 Oct 13.

Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, E03.511, PO Box 85500, 3508 GA Utrecht, The Netherlands.

Background: Anthracycline-induced cardiac dysfunction (ACD) is a notorious side effect of anticancer treatment. It has been described as a phenomenon of a continuous progressive decline of cardiac function, eventually leading to dilated cardiomyopathy (DCM). This progressive nature suggests that patients with a delayed ACD diagnosis have greater compromise of cardiac function and more adverse remodeling, with a poor response to heart failure (HF) treatment. This study aimed to delineate the impact of a delayed ACD diagnosis on echocardiographic characteristics and response to HF treatment.

Methods And Results: From the population of our cardio-oncology outpatient clinic, 92 ACD patients were included in this study (age 51.6 ± 16.2 years, median cumulative anthracycline dose 329 [200-329] mg/m), and a median follow-up of 25.0 [9.6-37.2] months after ACD diagnosis. Median time to ACD diagnosis for patients diagnosed early (< 1 year) and late (> 1 year) was 4.0 vs. 47.7 months respectively. There were no echocardiographic differences between patients diagnosed early vs. late (LVEF 43.6 ± 4.9% vs. 43.0 ± 6.2% and iEDV 63.6 vs. 62.9 mL/m). Eighty-three percent of patients presented with mild LV dysfunction and in 79% the LV was not dilated. Patients diagnosed early were more likely to have (partial) recovery of cardiac function upon HF treatment initiation ( = 0.015).

Conclusions: In the setting of a cardio-oncology outpatient clinic, patients with ACD presented with a hypokinetic non-dilated cardiomyopathy, rather than typical DCM. Timing of ACD diagnosis did not impact HF disease severity. However, in patients receiving an early diagnosis, cardiac function was more likely to recover upon HF treatment.
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http://dx.doi.org/10.1186/s40959-020-00079-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557080PMC
October 2020

Pulmonary Vein Isolation With Single Pulse Irreversible Electroporation: A First in Human Study in 10 Patients With Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2020 10 8;13(10):e008192. Epub 2020 Sep 8.

Department of Cardiology, University Medical Centre Utrecht, the Netherlands (P.L., R.v.E., M.H.A.G., W.K., F.H.M.W., P.A.D.).

Background: Irreversible electroporation (IRE) is a promising new nonthermal ablation technology for pulmonary vein (PV) isolation in patients with atrial fibrillation. Experimental data suggest that IRE ablation produces large enough lesions without the risk of PV stenosis, artery, nerve, or esophageal damage. This study aimed to investigate the feasibility and safety of single pulse IRE PV isolation in patients with atrial fibrillation.

Methods: Ten patients with symptomatic paroxysmal or persistent atrial fibrillation underwent single pulse IRE PV isolation under general anesthesia. Three-dimensional reconstruction and electroanatomical voltage mapping (EnSite Precision, Abbott) of left atrium and PVs were performed using a conventional circular mapping catheter. PV isolation was performed by delivering nonarcing, nonbarotraumatic 6 ms, 200 J direct current IRE applications via a custom nondeflectable 14-polar circular IRE ablation catheter with a variable hoop diameter (16-27 mm). A deflectable sheath (Agilis, Abbott) was used to maneuver the ablation catheter. A minimum of 2 IRE applications with slightly different catheter positions were delivered per vein to achieve circular tissue contact, even if PV potentials were abolished after the first application. Bidirectional PV isolation was confirmed with the circular mapping catheter and a post ablation voltage map. After a 30-minute waiting period, adenosine testing (30 mg) was used to reveal dormant PV conduction.

Results: All 40 PVs could be successfully isolated with a mean of 2.4±0.4 IRE applications per PV. Mean delivered peak voltage and peak current were 2154±59 V and 33.9±1.6 A, respectively. No PV reconnections occurred during the waiting period and adenosine testing. No periprocedural complications were observed.

Conclusions: In the 10 patients of this first-in-human study, acute bidirectional electrical PV isolation could be achieved safely by single pulse IRE ablation.
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http://dx.doi.org/10.1161/CIRCEP.119.008192DOI Listing
October 2020

Comparison of the Sapien 3 versus the ACURATE neo valve system: A propensity score analysis.

Catheter Cardiovasc Interv 2021 Mar 4;97(4):E597-E606. Epub 2020 Sep 4.

Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

Objectives: To compare the outcomes of transfemoral ACURATE neo (NEO) and Sapien 3 (S3) patients in terms of device success and clinical safety outcomes using a propensity score analysis.

Background: Differences in clinical outcomes between the latest-generation balloon-expandable S3 and self-expanding NEO in a "real-world transfemoral TAVI population" are still unclear.

Methods: We compared up to 6 months clinical outcomes using a propensity score analysis (inverse probability of treatment weighting [IPTW]) to account for differences in baseline characteristics.

Results: A total of 345 patients underwent transfemoral transcatheter aortic valve implantation (TAVI) with either NEO or S3 at two centers in the Netherlands. Composite device success and early safety endpoints were comparable between NEO and S3 (Device success: IPTW-adjusted OR: 0.35 [95% CI: 0.12-1.18], and early safety: IPTW-adjusted OR: 0.51 [95% CI: 0.19-1.38]). Six-months mortality was 5.3 versus 3.6%, stroke was 2.8 versus 3.3%, and pacemaker rate was 6.1 versus 8.6%, respectively with p = NS. Mean aortic gradient was lower in the NEO group (5.72 ± 2.47 vs. 9.05 ± 3.48; p = <.001), with a comparable rate of moderate or severe paravalvular leak (0 versus 2.1%; p = NS).

Conclusions: Device success and clinical safety outcomes were comparable for both valves. Up to 6-months follow-up clinical outcomes and mortality rate remained excellent. Mean aortic gradient was lower after ACURATE neo implantation.
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http://dx.doi.org/10.1002/ccd.29240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984444PMC
March 2021

Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2.

Front Cardiovasc Med 2020 28;7:115. Epub 2020 Jul 28.

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

Rheumatic heart disease (RHD) is common in developing countries and poses a big medical challenge and burden. The pathogenesis of RHD is influenced by the triad of host, agent, and environment. Autoantigens generated from Group A Streptococcus (GAS) infection are captured by the resident dendritic cells (DCs) in the heart's valvular endothelium. DCs differentiate into antigen presenting cells (APC) in the valve interstices. APC induces activation of autoreactive T cells, which triggers inflammation and tissue fibrosis. Cardiac fibrosis is promoted through the activation of Mitogen activated protein kinases (MAPKs) and its downstream signaling, including its interaction with transforming growth factor-β (TGF-β) and Smad proteins. TGF-β-induced phosphorylation of Smad2 complexes with Smad3 and Smad4, and translocates into the nucleus. Angiotensin II enhances the migration, maturation, and presentation of DC. In RHD, Angiotensin II induces fibrosis via the stimulation of TGF-β, which further increases the binding of IL-33 to sST2 but not ST2L, resulting in the upregulation of Angiotensin II and progression of cardiac fibrosis. This cascade of inflammation and valvular fibrosis causes calcification and stiffening of the heart valves in RHD. Angiotensin converting enzyme inhibitors (ACEIs) inhibit Angiotensin II production, which in turn decreases TGF-β expression and the onset of overt inflammatory response. This condition leads to a reduction in the sST2 as the decoy receptor to "steal" IL-33, and IL-33 binds to ST2L and results in cardioprotection against cardiac fibrosis in the pathogenesis of RHD.
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http://dx.doi.org/10.3389/fcvm.2020.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399157PMC
July 2020

Cellular and Molecular Mechanism of Cardiac Regeneration: A Comparison of Newts, Zebrafish, and Mammals.

Biomolecules 2020 08 19;10(9). Epub 2020 Aug 19.

Department of Cardiology, Experimental Cardiology Laboratory, UMC Utrecht, 3584CX Utrecht, The Netherlands.

Cardiovascular disease is the leading cause of death worldwide. Current palliative treatments can slow the progression of heart failure, but ultimately, the only curative treatment for end-stage heart failure is heart transplantation, which is only available for a minority of patients due to lack of donors' hearts. Explorative research has shown the replacement of the damaged and lost myocardium by inducing cardiac regeneration from preexisting myocardial cells. Lower vertebrates, such as the newt and zebrafish, can regenerate lost myocardium through cardiomyocyte proliferation. The preexisting adult cardiomyocytes replace the lost cells through subsequent dedifferentiation, proliferation, migration, and re-differentiation. Similarly, neonatal mice show complete cardiac regeneration post-injury; however, this regenerative capacity is remarkably diminished one week after birth. In contrast, the adult mammalian heart presents a fibrotic rather than a regenerative response and only shows signs of partial pathological cardiomyocyte dedifferentiation after injury. In this review, we explore the cellular and molecular responses to myocardial insults in different adult species to give insights for future interventional directions by which one can promote or activate cardiac regeneration in mammals.
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http://dx.doi.org/10.3390/biom10091204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564143PMC
August 2020

Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes.

Cell Stem Cell 2020 07;27(1):50-63.e5

DeVos Cardiovascular Research Program of Spectrum Health and Van Andel Research Institute, 100 Michigan Street NE, Grand Rapids, MI 49503, USA; Michigan State University, College of Human Medicine, 15 Michigan Street NE, Grand Rapids, MI, USA.

Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (<5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.e., 100- to 250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition using CHIR99021 and concurrent removal of cell-cell contact. We show that GSK-3β inhibition suppresses CM maturation, while contact removal prevents CMs from cell cycle exit. Remarkably, contact removal enabled 10 to 25 times greater expansion beyond GSK-3β inhibition alone. Mechanistically, persistent CM proliferation required both LEF/TCF activity and AKT phosphorylation but was independent from yes-associated protein (YAP) signaling. Engineered heart tissues from expanded hiPSC-CMs showed comparable contractility to those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionality after expansion. In summary, we uncovered a molecular interplay that enables massive hiPSC-CM expansion for large-scale drug screening and tissue engineering applications.
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http://dx.doi.org/10.1016/j.stem.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334437PMC
July 2020

Loss of miR-132/212 Has No Long-Term Beneficial Effect on Cardiac Function After Permanent Coronary Occlusion in Mice.

Front Physiol 2020 16;11:590. Epub 2020 Jun 16.

Department of Cardiology, Experimental Cardiology Laboratory, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.

Myocardial infarction (MI) is caused by occlusion of the coronary artery and induces ischemia in the myocardium and eventually a massive loss in cardiomyocytes. Studies have shown many factors or treatments that can affect the healing and remodeling of the heart upon infarction, leading to better cardiac performance and clinical outcome. Previously, miR-132/212 has been shown to play an important role in arteriogenesis in a mouse model of hindlimb ischemia and in the regulation of cardiac contractility in hypertrophic cardiomyopathy in mice. In this study, we explored the role of miR-132/212 during ischemia in a murine MI model. miR-132/212 knockout mice show enhanced cardiac contractile function at baseline compared to wild-type controls, as assessed by echocardiography. One day after induction of MI by permanent occlusion, miR-132/212 knockout mice display similar levels of cardiac damage as wild-type controls, as demonstrated by infarction size quantification and LDH release, although a trend toward more cardiomyocyte cell death was observed in the knockout mice as shown by TUNEL staining. Four weeks after MI, miR-132/212 knockout mice show no differences in terms of cardiac function, expression of cardiac stress markers, and fibrotic remodeling, although vascularization was reduced. In line with these observation, overexpression of miR-132 or miR-212 in neonatal rat cardiomyocyte suppress hypoxia induced cardiomyocyte cell death. Although we previously observed a role in collateral formation and myocardial contractility, the absence of miR-132/212 did not affect the overall myocardial performance upon a permanent occlusion of the coronary artery. This suggests an interplay of different roles of this miR-132/212 before and during MI, including an inhibitory effect on cell death and angiogenesis, and a positive effect on cardiac contractility and autophagic response. Thus, spatial or tissue specific manipulation of this microRNA family may be essential to fully understand the roles and to develop interventions to reduce infarct size.
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http://dx.doi.org/10.3389/fphys.2020.00590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309700PMC
June 2020

Epinephrine stress testing during cardiac catheterization in patients with aortic coarctation.

Am Heart J 2020 07 13;225:78-87. Epub 2020 May 13.

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

Background: The severity of aortic coarctation (CoA) may be underestimated during cardiac catheterization. We aimed to investigate whether epinephrine stress testing improves clinical decision making and outcome in CoA.

Methods: We retrospectively evaluated CoA patients >50 kg with a peak systolic gradient (PSG) ≤20 mm Hg during cardiac catheterization who underwent epinephrine stress testing. Subsequent interventional management (stenting or balloon dilatation), complications, and medium-term clinical outcome were assessed.

Results: Fifty CoA patients underwent cardiac catheterization with epinephrine stress testing. Patients with a high epinephrine PSG (>20 mm Hg; n = 24) were younger and more likely to have a hypertensive response to exercise compared to patients with a low epinephrine PSG (≤20 mm Hg; n = 26). In total, 21 patients (88%) with a high epinephrine PSG underwent intervention, and 20 patients (77%) with a low epinephrine PSG were treated conservatively. After a mean follow-up of 25 ± 18 months, there was a lower prevalence of hypertension in patients with a high epinephrine PSG who underwent intervention compared to patients with a low epinephrine PSG treated conservatively (19% vs. 76%; P = .001). In a multivariate model, intervention was independently associated with a 14.3-mm Hg reduction in systolic blood pressure (P = .001) and a decrease in the use of antihypertensive agents.

Conclusions: In CoA patients with a low baseline PSG but high epinephrine PSG, percutaneous intervention is associated with a substantial reduction in systemic blood pressure and the use of antihypertensive medication. Accordingly, epinephrine stress testing may be a useful addition in the evaluation of CoA.
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http://dx.doi.org/10.1016/j.ahj.2020.05.007DOI Listing
July 2020

Automatic Triage of 12-Lead ECGs Using Deep Convolutional Neural Networks.

J Am Heart Assoc 2020 05 14;9(10):e015138. Epub 2020 May 14.

Department of Cardiology University Medical Center Utrecht Utrecht The Netherlands.

BACKGROUND The correct interpretation of the ECG is pivotal for the accurate diagnosis of many cardiac abnormalities, and conventional computerized interpretation has not been able to reach physician-level accuracy in detecting (acute) cardiac abnormalities. This study aims to develop and validate a deep neural network for comprehensive automated ECG triage in daily practice. METHODS AND RESULTS We developed a 37-layer convolutional residual deep neural network on a data set of free-text physician-annotated 12-lead ECGs. The deep neural network was trained on a data set with 336.835 recordings from 142.040 patients and validated on an independent validation data set (n=984), annotated by a panel of 5 cardiologists electrophysiologists. The 12-lead ECGs were acquired in all noncardiology departments of the University Medical Center Utrecht. The algorithm learned to classify these ECGs into the following 4 triage categories: normal, abnormal not acute, subacute, and acute. Discriminative performance is presented with overall and category-specific concordance statistics, polytomous discrimination indexes, sensitivities, specificities, and positive and negative predictive values. The patients in the validation data set had a mean age of 60.4 years and 54.3% were men. The deep neural network showed excellent overall discrimination with an overall concordance statistic of 0.93 (95% CI, 0.92-0.95) and a polytomous discriminatory index of 0.83 (95% CI, 0.79-0.87). CONCLUSIONS This study demonstrates that an end-to-end deep neural network can be accurately trained on unstructured free-text physician annotations and used to consistently triage 12-lead ECGs. When further fine-tuned with other clinical outcomes and externally validated in clinical practice, the demonstrated deep learning-based ECG interpretation can potentially improve time to treatment and decrease healthcare burden.
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http://dx.doi.org/10.1161/JAHA.119.015138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660886PMC
May 2020

Echocardiography and MRI parameters associated with exercise capacity in patients after the arterial switch operation.

J Cardiol 2020 09 10;76(3):280-286. Epub 2020 May 10.

University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Background: The arterial switch operation (ASO) for transposition of the great arteries has excellent survival, but a substantial number of patients suffer from a reduced exercise capacity. The goal of this study was to identify imaging parameters associated with a reduced exercise capacity in patients after ASO.

Methods: A retrospective analysis was performed of ASO patients who underwent cardiopulmonary exercise testing (CPET) between 2007 and 2017. Reduced exercise performance was defined as a reduced workload peak (W) with Z-score <-2 or a peak oxygen uptake indexed for weight (VO/kg) with Z-score <-2. Data on echocardiography and cardiac magnetic resonance performed within 1 year of the CPET were collected for comparison.

Results: A total of 81 ASO patients (age 17±7 years) were included. Reduced exercise performance was found in 22 patients (27%) as expressed by either a reduced W and/or a reduced VO/kg. Main pulmonary artery gradient and tricuspid regurgitation gradient by echocardiography were found to be associated with reduced W (p=0.031; p=0.020, respectively). The main pulmonary artery gradient and tricuspid regurgitation gradient by echocardiography were found to be associated with reduced VO/kg (p=0.009; p=0.019, respectively). No left ventricular parameters were found to be associated with abnormal exercise performance.

Conclusion: This study demonstrates that ASO patients frequently experience reduced exercise capacity. Echocardiographic evidence of main pulmonary artery stenosis and increased right ventricular pressure were associated with reduced exercise capacity, and are therefore key to monitor during serial follow-up of ASO patients.
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http://dx.doi.org/10.1016/j.jjcc.2020.02.025DOI Listing
September 2020

The utility of the oxygen pulse recovery as a marker of the cardiac output response to exercise in patients with chronic heart failure.

Clin Physiol Funct Imaging 2020 Sep 4;40(5):328-335. Epub 2020 Jun 4.

Department of Cardiology, Máxima Medical Center, Veldhoven, The Netherlands.

Purpose: The cardiac output (CO) response to exercise is a useful marker to grade the prognosis and severity of chronic heart failure (CHF). The recovery of the oxygen pulse (OP) is a non-invasive parameter, which is related to exercise capacity in cardiac patients. However, the relation between OP recovery and the central haemodynamic response to exercise remains to be determined. We hypothesized that an impaired OP recovery is associated with a reduced CO response to exercise in CHF patients.

Methods: Sixty one CHF patients performed cardiopulmonary exercise test with simultaneous measurement of CO. Impaired OP recovery was defined as an overshoot during the first minute of recovery or OP at 1-min recovery as a percentage of peak OP (OP ).

Results: An OP overshoot was observed in 9% (n = 5) of patients. In these patients, peak CO and VO were significantly lower (peak CO 7.9 ± 0.8 versus 11.2 ± 4.3 L/min and peak VO 14.1 ± 4.7 versus 19.6 ± 5.8 ml min  kg ). Mean relative recovery of OP was 78 ± 20%. Slow OP recovery (negative OP ) was seen in 13% (n = 8). Peak CO and VO were significantly lower in the negative OP group (11 ± 4 versus 8 ± 0.7 L/min and 19.7 ± 5.9 versus 14.6 ± 3.7 ml kg min ). There was a significant relation between OP and stroke volume (SV) (r = .57), as well as between OP and a-v O diff (r  = .4).

Conclusion: An impaired OP recovery is associated with a reduced CO response to exercise and worse functional status. Therefore, the OP recovery can be used to grade the severity of CHF.
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http://dx.doi.org/10.1111/cpf.12639DOI Listing
September 2020

Development of an algorithm for automatic classification of right ventricle deformation patterns in arrhythmogenic right ventricular cardiomyopathy.

Echocardiography 2020 05 3;37(5):698-705. Epub 2020 May 3.

Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

Background: Different disease stages of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be identified by right ventricle (RV) longitudinal deformation (strain) patterns. This requires assessment of the onset of shortening, (systolic) peak strain, and postsystolic index, which is time-consuming and prone to inter- and intra-observer variability. The aim of this study was to design and validate an algorithm to automatically classify RV deformation patterns.

Methods: We developed an algorithm based on specific local characteristics from the strain curves to detect the parameters required for classification. Determination of the onset of shortening by the algorithm was compared to manual determination by an experienced operator in a dataset containing 186 RV strain curves from 26 subjects carrying a pathogenic plakophilin-2 (PKP2) mutation and 36 healthy subjects. Classification agreement between operator and algorithm was solely based on differences in onset shortening, as the remaining parameters required for classification of RV deformation patterns could be directly obtained from the strain curves.

Results: The median difference between the onset of shortening determined by the experienced operator and by the automatic detector was 5.3 ms [inter-quartile range (IQR) 2.7-8.6 ms]. 96% of the differences were within 1 time frame. Both methods correlated significantly with ρ = 0.97 (P < .001). For 26 PKP2 mutation carriers, there was 100% agreement in classification between the algorithm and experienced operator.

Conclusion: The determination of the onset of shortening by the experienced operator was comparable to the algorithm. Our computer algorithm seems a promising method for the automatic classification of RV deformation patterns. The algorithm is publicly available at the MathWorks File Exchange.
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http://dx.doi.org/10.1111/echo.14671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317368PMC
May 2020

Control of Angiogenesis via a VHL/miR-212/132 Axis.

Cells 2020 04 19;9(4). Epub 2020 Apr 19.

Department of Nephrology & Hypertension, Division Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.
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http://dx.doi.org/10.3390/cells9041017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226144PMC
April 2020

Cardiomyocyte Specific Deletion of ADAR1 Causes Severe Cardiac Dysfunction and Increased Lethality.

Front Cardiovasc Med 2020 18;7:30. Epub 2020 Mar 18.

Laboratory of Experimental Cardiology, Circulatory Health Laboratory, Department of Cardiology, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands.

Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that is involved in several functions including the deamination of adenosine to inosine, RNA interference (RNAi) mechanisms and microRNA (miRNA) processing, rendering ADAR1 essential for life. To investigate whether maintenance of ADAR1 expression is required for normal myocardial homeostasis, we bypassed the early embryonic lethality of ADAR1-null mice through the use of a tamoxifen-inducible Cre recombinase under the control of the cardiac-specific α-myosin heavy chain promoter (αMHC). Targeted ADAR1 deletion in adult mice caused a significant increase in lethality accompanied by severe ventricular remodeling and quick and spontaneous cardiac dysfunction, induction of stress markers and overall reduced expression of miRNAs. Administration of a selective inhibitor of the unfolded protein response (UPR) stress significantly blunted the deleterious effects and improved cardiac function thereby prolonging animal survival. restoring miR-199a-5p levels in cardiomyocytes lacking ADAR1 diminished UPR activation and concomitant apoptosis. Our findings demonstrate an essential role for ADAR1 in cardiomyocyte survival and maintenance of cardiac function through a mechanism that integrates ADAR1 dependent miRNA processing and the suppression of UPR stress.
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http://dx.doi.org/10.3389/fcvm.2020.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093378PMC
March 2020

Prognostic biomarker soluble ST2 exhibits diurnal variation in chronic heart failure patients.

ESC Heart Fail 2020 06 31;7(3):1224-1233. Epub 2020 Mar 31.

Department of Cardiology, Experimental Cardiology Laboratory, University Medical Centre Utrecht, Utrecht, The Netherlands.

Aim: Soluble suppression of tumorigenicity-2 (sST2) is a strong prognostic biomarker in heart failure. The emerging understanding of circadian biology in cardiovascular disease may lead to novel applications in prognosis and diagnosis and may provide insight into mechanistic aspects of the disease-biomarker interaction. So far, it is unknown whether sST2 exhibits a diurnal rhythm. Repeated measurements of sST2 may aid in clinical decision making. The goal of this study was to investigate whether sST2 exhibits diurnal variation in patients with heart failure with reduced ejection fraction (HFrEF) and in control subjects, thereby enhancing its diagnostic and prognostic values.

Methods And Results: The study comprised 32 subjects: 16 HFrEF patients and 16 controls. Blood was collected at seven subsequent time points during a 24 h time period. sST2, N-terminal pro-B-type natriuretic peptide (NT-proBNP), melatonin, and cortisol were measured from serum. Peak values of sST2 clustered at daytime (modal value: 5 p.m.) in 87.6% of all subjects (81.3% of patients, P = 0.021; 93.8% of controls, P = 0.001), and minimum concentrations at night-time (modal value: 5 a.m.) in 84.4% (87.5% of patients, P = 0.004 81.3% of controls, P = 0.021). A cosinor analysis of mean normalized sST2 values revealed significant cosine shaped 24 h oscillations of patients (P = 0.026) and controls (P = 0.037). NT-proBNP in contrast did not show a diurnal rhythm, while melatonin and cortisol patterns were intact in all subjects.

Conclusions: sST2 exhibits a diurnal rhythm with lower values in the morning than in the late afternoon. This new insight could lead to refinement of its diagnostic and prognostic values through specified and consistent sampling times with repeated measurements. For example, by measuring sST2 during the afternoon, when levels are at their highest, false negatives on prognosis prediction could be avoided.
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http://dx.doi.org/10.1002/ehf2.12673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261542PMC
June 2020

Cardiovascular adverse events in patients with non-Hodgkin lymphoma treated with first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP): a systematic review and meta-analysis.

Lancet Haematol 2020 Apr 2;7(4):e295-e308. Epub 2020 Mar 2.

Department of Cardiology, Division of Heart and Lungs, University Medical Centre Utrecht, University of Utrecht, Utrecht, Netherlands; Netherlands Heart Institute, Utrecht, Netherlands; Health Data Research UK, Institute of Health Informatics and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.

Background: Patients treated for non-Hodgkin lymphoma are at risk of cardiovascular adverse events, with the risk of heart failure being particularly high. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with (R-CHOP) or without (CHOP) rituximab is the standard first-line treatment for aggressive non-Hodgkin lymphoma, and doxorubicin and cyclophosphamide are both associated with left ventricular dysfunction. The aim of this systematic review and meta-analysis was to evaluate the cardiovascular toxicity of this regimen.

Methods: We systematically searched PubMed, EMBASE, and the Cochrane Library from database inception to June 3, 2019, for clinical trials and observational studies in adult patients with non-Hodgkin lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and non-Hodgkin lymphoma not otherwise specified) that received first-line treatment with R-CHOP or CHOP. Studies reporting on cardiovascular adverse events and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3-4 cardiovascular adverse events and heart failure. Meta-analyses of one-sample proportions were done in all patients receiving CHOP or R-CHOP. Subgroup analyses on summary estimates were done to determine the effect of number of CHOP or R-CHOP cycles, cycle interval, age, and sex.

Findings: Of 2314 identified entries, 137 studies (21 211 patients) published between April, 1984, and June, 2019 were eligible (9541 patients treated with CHOP, 11 293 patients treated with R-CHOP, 377 both regimens used in the study; median follow-up 39·0 months [IQR 25·5-52·8]). From the included studies, 85 subgroups were treated with CHOP, 76 with R-CHOP, and in four studies both CHOP and R-CHOP were used without a subdivision in separate groups. The pooled proportion for grade 3-4 cardiovascular adverse events, based on 77 studies (n=14 351 patients), was 2·35% (95% CI 1·81-2·93; heterogeneity test Q=326·21; τ=0·0042; I=71·40%; p<0·0001). For heart failure, the pooled proportion, based on 38 studies (n=5936 patients), was 4·62% (2·25-7·65; heterogeneity test Q=527·33; τ=0·0384; I=95·05%; p<0·0001), with a significant increase in reported heart failure from 1·64% (95% CI 0·82-2·65) to 11·72% (3·00-24·53) when cardiac function was evaluated post-chemotherapy (p=0·017). 53 (39%) of 137 studies were rated as having high risk of bias for incomplete outcome data and 54 (39%) for selective reporting.

Interpretation: The considerable increase of reported heart failures with cardiac monitoring, indicates that this complication often remains undiagnosed in patients with non-Hodgkin lymphoma who received first-line R-CHOP or CHOP. Our findings are of importance to raise awareness of this complication among clinicians treating patients with non-Hodgkin lymphoma and stresses the need for cardiac monitoring during and after chemotherapy. Prompt initiation of treatment for heart failure in the presymptomatic phase can mitigate the progression to more advanced heart failure stages.

Funding: None.
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http://dx.doi.org/10.1016/S2352-3026(20)30031-4DOI Listing
April 2020

Potential of mesenchymal- and cardiac progenitor cells for therapeutic targeting of B-cells and antibody responses in end-stage heart failure.

PLoS One 2019 31;14(12):e0227283. Epub 2019 Dec 31.

Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.

Upon myocardial damage, the release of cardiac proteins induces a strong antibody-mediated immune response, which can lead to adverse cardiac remodeling and eventually heart failure (HF). Stem cell therapy using mesenchymal stromal cells (MSCs) or cardiomyocyte progenitor cells (CPCs) previously showed beneficial effects on cardiac function despite low engraftment in the heart. Paracrine mediators are likely of great importance, where, for example, MSC-derived extracellular vesicles (EVs) also show immunosuppressive properties in vitro. However, the limited capacity of MSCs to differentiate into cardiac cells and the sufficient scaling of MSC-derived EVs remain a challenge to clinical translation. Therefore, we investigated the immunosuppressive actions of endogenous CPCs and CPC-derived EVs on antibody production in vitro, using both healthy controls and end-stage HF patients. Both MSCs and CPCs strongly inhibit lymphocyte proliferation and antibody production in vitro. Furthermore, CPC-derived EVs significantly lowered the levels of IgG1, IgG4, and IgM, especially when administered for longer duration. In line with previous findings, plasma cells of end-stage HF patients showed high production of IgG3, which can be inhibited by MSCs in vitro. MSCs and CPCs inhibit in vitro antibody production of both healthy and end-stage HF-derived immune cells. CPC-derived paracrine factors, such as EVs, show similar effects, but do not provide the complete immunosuppressive capacity of CPCs. The strongest immunosuppressive effects were observed using MSCs, suggesting that MSCs might be the best candidates for therapeutic targeting of B-cell responses in HF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227283PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938331PMC
April 2020
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