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Aims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation. Methods and results We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1–2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0–3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality. Conclusion Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.

Aims Cardiac sarcoidosis (CS) is a known cause of ventricular tachycardia (VT). However, an arrhythmogenic presentation may not prompt immediate comprehensive evaluation. We aimed to assess the diagnostic and disease course of patients with arrhythmogenic cardiac sarcoidosis (ACS). Methods and results From the Leiden VT-ablation-registry, consecutive patients with CS as underlying aetiology were retrospectively included. Data on clinical presentation, time-to-diagnosis, cardiac function, and clinical outcomes were collected. Patients were divided in early (, Graphical Abstract Graphical Abstract

We present a patient with fever-induced Brugada syndrome, a rare cardiac disease caused by an inherited ion channelopathy and associated with malignant arrhythmias. ECG findings normalized after the fever resolved. As Brugada syndrome can be confused with anterior myocardial ischemia, right bundle branch block and intoxication with tricyclic antidepressants, ECG recognition is important. Patients with Brugada syndrome are instructed to avoid contraindicated substances, and fever should be treated aggressively.

Background Recently published randomised clinical trials indicate that prolonged electrocardiom (ECG) monitoring might enhance the detection of paroxysmal atrial fibrillation (AF) in cryptogenic stroke or transient ischaemic attack (TIA) patients. A device that might be suitable for prolonged ECG monitoring is a smartphone-compatible ECG device (Kardia Mobile, Alivecor, San Francisco, CA, USA) that allows the patient to record a single-lead ECG without the presence of trained health care staff. The MOBILE-AF trial will investigate the effectiveness of the ECG device for AF detection in patients with cryptogenic stroke or TIA. In this paper, the rationale and design of the MOBILE-AF trial is presented. Methods For this international, multicentre trial, 200 patients with cryptogenic stroke or TIA will be randomised. One hundred patients will receive the ECG device and will be asked to record their ECG twice daily during a period of 1 year. One hundred patients will receive a 7-day Holter monitor. Discussion The primary outcome of this study is the percentage of patients in which AF is detected in the first year after the index ischaemic stroke or TIA. Secondary outcomes include markers for AF prediction, orally administered anticoagulation therapy changes, as well as the incidence of recurrent stroke and major bleeds. First results can be expected in mid-2019. Trial registration ClinicalTrials.gov, ID: NCT02507986. Registered on 15 July 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2131-0) contains supplementary material, which is available to authorized users.

OBJECTIVE: Cholesterol ester transfer protein (CETP) plays an important role in HDL cholesterol metabolism. Leucocytes, including monocyte-derived macrophages in the arterial wall synthesize and secrete CETP, but its role in atherosclerosis is unclear. The aim of the current study was to investigate the effect of acute coronary syndromes (ACS) on leucocyte CETP expression.RESEARCH DESIGN: Peripheral blood mononuclear cells (PBMCs) were freshly isolated from hospitalized ACS patients displaying Braunwald class IIIB unstable angina pectoris (UAP) on admission (t = 0) and at 180 days post inclusion (t = 180) for analysis of CETP expression. In addition, to prove the potential correlation between leucocyte CETP and ACS the effect of acute myocardial infarction on leucocyte CETP expression was studied in CETP transgenic mice.RESULTS: Upon admission, UAP patients displayed approximately 3-6 fold (P < 0.01) lower CETP mRNA and nearly absent CETP protein expression in PBMCs, as compared to healthy age-/sex-matched controls. Interestingly, CETP mRNA and protein levels were significantly elevated in PBMCs isolated from UAP patients (both stabilized and refractory) at t = 180 as compared to t = 0 (P < 0.01), which was correlated with a reduced inflammatory status after medical treatment. In agreement with the data obtained in UAP patients, markedly down-regulated leucocyte CETP mRNA expression was observed after coronary artery ligation in CETP transgenic mice, which also correlated with increased serum amyloid A levels.CONCLUSIONS: We are the first to report that episodes of UAP in humans and myocardial infarction in CETP transgenic mice are associated with reduced leucocyte CETP expression. We propose that the impairment in leucocyte CETP production is associated with an enhanced inflammatory status, which could be clinically relevant for the pathogenesis of ACS.

Persistent ductus arteriosus (PDA) is a common cardiovascular anomaly in children caused by the pathologic persistence of the left sixth pharyngeal arch artery. The inbred Brown-Norway (BN) rat presents with increased vascular fragility due to an aortic elastin deficit resulting from decreased elastin synthesis. The strikingly high prevalence of PDA in BN rats in a pilot study led us to investigate this vascular anomaly in 12 adolescent BN rats. In all BN rats, a PDA was observed macroscopically, whereas a ligamentum arteriosum was found in adult controls. The macroscopic appearance of the PDA was tubular (n = 2), stenotic (n = 8), or diverticular (n = 2). The PDA had the structure of a muscular artery with intimal thickening. In the normal closing ductus of the neonatal controls, the media consisted of layers of smooth muscle cells (SMCs) intermingled with layers of elastin. The intima was thin and poor in elastin. By contrast, the media of PDA in BN rats elastin lamellae were absent and the intima contained many elastic fibers. The abnormal distribution of elastin in the PDA of BN rats suggests that impaired elastin metabolism is related to the persistence of the ductus and implicates a genetically determined factor that may link the PDA with aortic fragility.

Objective: Several decellularisation techniques have been developed to produce acellular matrix scaffolds for the purpose of tissue engineering, mostly comprising (non-)ionic detergents or enzymatic extraction methods. However, the effect of chemically induced decellularisation on the major structural and adhesion molecules as well as glycosaminoglycans, and the possible replenishment of lost compounds have escaped attention. Methods: Porcine aortic valves were treated with two different methods: detergent Triton X-100 and enzymatic Trypsine cell extraction. (Immuno-) histochemistry was used to address changes in extracellular matrix constitution (elastin, collagen, glycosaminoglycans, chondroitin sulfate, fibronectin and laminin) and the production of extracellular matrix components by seeded endothelial cells. Results: The Trypsine treated group showed a fragmentation and distortion of elastic fibers. Changes in collagen distribution were observed in both groups. An almost complete washout of glycosaminoglycans and chondroitin sulfate was observed in the Triton and Trypsin treated group, but the latter with a smaller glycosaminoglycans reduction. Both treatments resulted in a considerable washout of the adhesion molecules laminin and fibronectin. Furthermore, seeded endothelial cells were capable of synthesising laminin, fibronectin and chondroitin sulfate. Conclusions: Chemically induced decellularisation by Triton or Trypsine resulted in changes in the extracellular matrix constitution, which could lead to problems in valve functionality and cell growth and migration. Seeded endothelial cells were capable of synthesising extracellular matrix components lost by cell extraction. Further studies on tissue engineering should focus more on the effect of chemically induced cell extraction on the extracellular matrix of the remaining scaffold and the in vitro or in vivo replenishment of lost compounds.

Introduction: We previously showed that human cardiomyocyte progenitor cells (hCMPCs) injected after myocardial infarction (MI) had differentiated into cardiomyocytes in vivo 3 months post MI. Here, we investigated the short-term (2 weeks) effects of hCMPCs on the infarcted mouse myocardium. Methods: MI was induced in immunocompromised (NOD/scid) mice, immediately followed by intramyocardial injection of hCMPCs labeled with enhanced green fluorescent protein (hCMPC group) or vehicle only (control group). Sham-operated mice served as reference. Cardiac performance was measured 2 and 14 days after MI by magnetic resonance imaging at 9.4T. Left ventricular (LV) pressure-volume measurements were performed at day 15 followed by extensive immunohistological analysis. Results: Animals injected with hCMPCs demonstrated a higher LV ejection fraction, lower LV end-systolic volume and smaller relaxation time constant than control animals 14 days post MI. hCMPCs engrafted in the infarcted myocardium, did not differentiate into cardiomyocytes, but increased vascular density and proliferation rate in the infarcted and border zone area of the hCMPC group. Conclusions: Injected hCMPCs engraft into murine infarcted myocardium where they improve LV systolic function and attenuate the ventricular remodeling process 2 weeks post MI. Since no cardiac differentiation of hCMPCs was evident after 2 weeks, the observed beneficial effects were most likely mediated by paracrine factors, targeting amongst others vascular homeostasis. These results demonstrate that hCMPCs can be applied to repair infarcted myocardium without the need to undergo differentiation into cardiomyocytes.

As chemokines are considered instrumental in thrombotic plaque rupture and erosion as well as in ischemia-reperfusion injury processes, we aimed to identify previously unknown chemokines associated with acute coronary syndromes. Plasma of 44 patients with acute myocardial infarction (AMI) and 22 controls were profiled for a panel of chemokines by multiplex analysis. Levels of CCL3 were prospectively verified in 54 patients with unstable angina pectoris (UAP). An AMI mouse model was used to assess the relationship between differentially expressed chemokines and myocardial ischemia. CCL3 levels were significantly elevated in AMI vs. controls (P=0.02) albeit, that adjustment for confounding factors attenuated this association. In support of a direct association with cardiac ischemia CCL3 levels were also seen to be elevated in patients with UAP at baseline and significantly down-regulated after 180 days (P

Aim: Murine myocardial infarction (MI) models are increasingly used in heart failure studies. Magnetic resonance imaging (MRI) and pressure–volume loops by conductance catheter (CC) enable physiological phenotyping. We performed a comparative analysis of MRI vs. CC to assess left ventricular (LV) function in the failing mouse heart. Methods: MI was created by LAD ligation. MRI (day 14) and CC (day 15) were used to determine LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF). Results: Pooled data yielded moderate-to-strong linear correlations: EDV: R = 0.61; ESV: R = 0.72; EF: R = 0.81. We analysed three groups, no MI (sham, n = 10), small MI ( 30%, n = 20). Volumes and EF were consistently lower by CC than by MRI, but group differences were evident for both techniques. Receiver-operating characteristic analysis indicated good sensitivity and specificity for both techniques, with superior results for MRI. Conclusions: CC and MRI are highly valuable for evaluation of LV volume and function. MRI is recommended for longitudinal studies, accurate absolute volumes and anatomical information. Unique features of CC are its online signal with high temporal resolution, and advanced analysis of LV function and energetics.

Human mesenchymal stem cells (hMSCs) have only a limited differentiation potential toward cardiomyocytes. Forced expression of the cardiomyogenic transcription factor myocardin may stimulate hMSCs to acquire a cardiomyogenic phenotype, thereby improving their possible therapeutic potential. hMSCs were transduced with green fluorescent protein (GFP) and myocardin (hMSCmyoc) or GFP and empty vector (hMSC). After coronary ligation in immune-compromised NOD/scid mice, hMSCmyoc (n = 10), hMSC (n = 10), or medium only (n = 12) was injected into the infarct area. Sham-operated mice (n = 12) were used to determine baseline characteristics. Left ventricular (LV) volumes and ejection fraction (EF) were serially (days 2 and 14) assessed using 9.4-T magnetic resonance imaging. LV pressure-volume measurements were performed at day 15, followed by histological evaluation. At day 2, no differences in infarct size, LV volumes, or EF were observed among the myocardial infarction groups. At day 14, left ventricular ejection fraction in both cell-treated groups was preserved compared with the nontreated group; in addition, hMSCmyoc injection also reduced LV volumes compared with medium injection (p < .05). Furthermore, pressure-volume measurements revealed a significantly better LV function after hMSCmyoc injection compared with hMSC treatment. Immunohistochemistry at day 15 demonstrated that the engraftment rate was higher in the hMSCmyoc group compared with the hMSC group (p < .05). Furthermore, these cells expressed a number of cardiomyocyte-specific markers not observed in the hMSC group. After myocardial infarction, injection of hMSCmyoc improved LV function and limited LV remodeling, effects not observed after injection of hMSC. Furthermore, forced myocardin expression improved engraftment and induced a cardiomyocyte-like phenotype hMSC differentiation. Disclosure of potential conflicts of interest is found at the end of this article.

Background— Nonresponse to cardiac resynchronization therapy is associated with the presence of slow or nonconducting scar tissue. Genetic modification of scar tissue, aimed at improving conduction, may be a novel approach to achieve effective resynchronization. Therefore, the feasibility of resynchronization with genetically modified human ventricular scar fibroblasts was studied in a coculture model. Methods and Results— An in vitro model was used to study the effects of forced expression of the myocardin ( MyoC ) gene in human ventricular scar fibroblasts (hVSFs) on resynchronization of 2 rat cardiomyocyte fields separated by a strip of hVSFs. Furthermore, the effects of MyoC expression on the capacity of hVSFs to serve as pacing sites were studied. MyoC-dependent gene activation in hVSFs was examined by gene and immunocytochemical analysis. Forced MyoC expression in hVSFs decreased dyssynchrony, expressed as the activation delay between 2 cardiomyocyte fields (control hVSFs 27.6±0.2 ms [n=11] versus MyoC-hVSFs 3.6±0.3 ms [n=11] at day 8, P MyoC expression in hVSFs led to the expression of various connexin and cardiac ion channel genes. Intracellular measurements of MyoC-hVSFs coupled to surrounding cardiomyocytes showed strongly improved action potential conduction. Conclusions— Forced MyoC gene expression in hVSFs allowed electrical stimulation of these cells and conferred the ability to conduct an electrical impulse at high velocity, which resulted in resynchronization of 2 separated cardiomyocyte fields. Both phenomena appear mediated mainly by MyoC-dependent activation of genes that encode connexins, strongly enforcing intercellular electrical coupling.

Background— Proper development of compact myocardium, coronary vessels, and Purkinje fibers depends on the presence of epicardium-derived cells (EPDCs) in embryonic myocardium. We hypothesized that adult human EPDCs might partly reactivate their embryonic program when transplanted into ischemic myocardium and improve cardiac performance after myocardial infarction. Methods and Results— EPDCs were isolated from human adult atrial tissue. Myocardial infarction was created in immunodeficient mice, followed by intramyocardial injection of 4×10 5 enhanced green fluorescent protein–labeled EPDCs (2-week survival, n=22; 6-week survival, n=15) or culture medium (n=24 and n=18, respectively). Left ventricular function was assessed with a 9.4T animal MRI unit. Ejection fraction was similar between groups on day 2 but was significantly higher in the EPDC-injected group at 2 weeks (short term), as well as after long-term survival at 6 weeks. End-systolic and end-diastolic volumes were significantly smaller in the EPDC-injected group than in the medium-injected group at all ages evaluated. At 2 weeks, vascularization was significantly increased in the EPDC-treated group, as was wall thickness, a development that might be explained by augmented DNA-damage repair activity in the infarcted area. Immunohistochemical analysis showed massive engraftment of injected EPDCs at 2 weeks, with expression of α-smooth muscle actin, von Willebrand factor, sarcoplasmic reticulum Ca 2+ -ATPase, and voltage-gated sodium channel (α-subunit; SCN5a). EPDCs were negative for cardiomyocyte markers. At 6-weeks survival, wall thickness was still increased, but only a few EPDCs could be detected. Conclusions— After transplantation into ischemic myocardium, adult human EPDCs preserve cardiac function and attenuate ventricular remodeling. Autologous human EPDCs are promising candidates for clinical application in infarcted hearts.

Mesenchymal stem cells (MSCs) from healthy donors improve cardiac function in experimental acute myocardial infarction (AMI) models. However, little is known about the therapeutic capacity of human MSCs (hMSCs) from patients with ischemic heart disease (IHD). Therefore, the behavior of hMSCs from IHD patients in an immune-compromised mouse AMI model was studied. Enhanced green fluorescent protein-labeled hMSCs from IHD patients (hMSC group: 2 × 105cells in 20 μl, n = 12) or vehicle only (medium group: n = 14) were injected into infarcted myocardium of NOD/ scid mice. Sham-operated mice were used as the control ( n = 10). Cardiac anatomy and function were serially assessed using 9.4-T magnetic resonance imaging (MRI); 2 wk after cell transplantation, immunohistological analysis was performed. At day 2, delayed-enhancement MRI showed no difference in myocardial infarction (MI) size between the hMSC and medium groups (33 ± 2% vs. 36 ± 2%; P = not significant). A comparable increase in left ventricular (LV) volume and decrease in ejection fraction (EF) was observed in both MI groups. However, at day 14, EF was higher in the hMSC than in the medium group (24 ± 3% vs. 16 ± 2%; P < 0.05). This was accompanied by increased vascularity and reduced thinning of the infarct scar. Engrafted hMSCs (4.1 ± 0.3% of injected cells) expressed von Willebrand factor (16.9 ± 2.7%) but no stringent cardiac or smooth muscle markers. hMSCs from patients with IHD engraft in infarcted mouse myocardium and preserve LV function 2 wk after AMI, potentially through an enhancement of scar vascularity and a reduction of wall thinning.

Objectives Decellularization of aortic valve allografts in advance of transplantation is a promising approach to overcome immune-induced early graft failure. In this study the effects of in vitro cell extraction on extracellular matrix molecules and in vivo remodeling of decellularized aortic valves were investigated in a heterotopic aortic valve rat implantation model. Methods Rat aortic valve conduits were decellularized by a 2-step detergent–enzymatic extraction method involving sodium dodecyl sulfate in combination with RNase and DNase. Cellular and acellular allogeneic (2×, n=4) and syngeneic valve grafts (2×, n=3) were grafted infrarenally into the descending aorta for 21 days. Immunohistochemical techniques were used to study extracellular matrix constitution (elastin, collagen, fibronectin, and chondroitin sulfate) and cellular infiltration. Results The decellularization procedure resulted in a complete loss of all cellular structures from the entire valve conduit with minimal damage to the extracellular matrix. All transplanted cellular allografts became deformed, swollen, and acellular with major changes in extracellular matrix structure. The transplanted decellularized allografts, however, retained normal preserved valve leaflets comparable to transplanted cellular and acellular syngeneic grafts. With the exception of cellular syngeneic grafts, all other grafts showed retrovalvular thrombi. Conclusions Damage to the valves caused by decellularization technique is much less than the damage caused by the recipient's immune response. In vitro removal of viable cells in (cryopreserved) homografts may decrease graft failure. Seeding with autologous or major histocompatibility complex–matched donor endothelial cells will be necessary to diminish damage induced by an absent blood-tissue barrier.