188 research outputs found
Evolution of priorities in strategic funding for collaborative health research. A comparison of the European Union Framework Programmes to the program funding by the United States National Institutes of Health
The historical research-funding model, based on the curiosity and academic
interests of researchers, is giving way to new strategic funding models that
seek to meet societal needs. We investigated the impact of this trend on health
research funded by the two leading funding bodies worldwide, i.e. the National
Institutes of Health (NIH) in the United States, and the framework programs of
the European Union (EU). To this end, we performed a quantitative analysis of
the content of projects supported through programmatic funding by the EU and
NIH, in the period 2008-2014 and 2015-2020. We used machine learning for
classification of projects as basic biomedical research, or as more
implementation directed clinical therapeutic research, diagnostics research,
population research, or policy and management research. In addition, we
analyzed funding for major disease areas (cancer, cardio-metabolic and
infectious disease). We found that EU collaborative health research projects
clearly shifted towards more implementation research. In the US, the recently
implemented UM1 program has a similar profile with strong clinical therapeutic
research, while other NIH programs remain heavily oriented to basic biomedical
research. Funding for cancer research is present across all NIH and EU
programs, and in biomedical as well as more implementation directed projects,
while infectious diseases is an emerging theme. We conclude that demand for
solutions for medical needs leads to expanded funding for implementation- and
impact-oriented research. Basic biomedical research remains present in programs
driven by scientific initiative and strategies based on excellence, but may be
at risk of declining funding opportunities
Myocyte remodeling due to fibro-fatty infiltrations influences arrhythmogenicity
The onset of cardiac arrhythmias depends on the electrophysiological and structural properties of cardiac tissue. Electrophysiological remodeling of myocytes due to the presence of adipocytes constitutes a possibly important pathway in the pathogenesis of atrial fibrillation. In this paper we perform an in-silico study of the effect of such myocyte remodeling on the onset of atrial arrhythmias and study the dynamics of arrhythmia sources-spiral waves. We use the Courtemanche model for atrial myocytes and modify their electrophysiological properties based on published cellular electrophysiological measurements in myocytes co-cultered with adipocytes (a 69-87 % increase in APD90 and an increase of the RMP by 2.5-5.5 mV). In a generic 2D setup we show that adipose tissue remodeling substantially affects the spiral wave dynamics resulting in complex arrhythmia and such arrhythmia can be initiated under high frequency pacing if the size of the remodeled tissue is sufficiently large. These results are confirmed in simulations with an anatomically accurate model of the human atria
Arrhythmogenicity of fibro-fatty infiltrations
The onset of cardiac arrhythmias depends on electrophysiological and structural properties of cardiac tissue. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. In this paper we investigate the arrhythmogenic mechanisms resulting from the presence of adipose tissue in the heart using computer modelling. We use the TP06 model for human ventricular cells and study how the size and percentage of adipose infiltrates affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset
Calcium/calmodulin-dependent kinase II and nitric oxide synthase 1 dependent modulation of ryanodine receptors during β-adrenergic stimulation is restricted to the dyadic cleft.
In cardiac myocytes, β‐adrenergic stimulation enhances Ca2+ cycling through an integrated signalling cascade modulating L‐type Ca2+ channels (LTCCs), phospholamban and ryanodine receptors (RyRs). Ca2+/calmodulin‐dependent kinase II (CaMKII) and nitric oxide synthase 1 (NOS1) are proposed as prime mediators for increasing RyR open probability. We investigate whether this pathway is confined to the high Ca2+ microdomain of the dyadic cleft and thus to coupled RyRs. Pig ventricular myocytes are studied under whole‐cell voltage‐clamp and confocal line‐scan imaging with Fluo‐4 as a [Ca2+]i indicator. Following conditioning depolarizing pulses, spontaneous RyR activity is recorded as Ca2+ sparks, which are assigned to coupled and non‐coupled RyR clusters. Isoproterenol (ISO) (10 nm) increases Ca2+ spark frequency in both populations of RyRs. However, CaMKII inhibition reduces spark frequency in coupled RyRs only; NOS1 inhibition mimics the effect of CaMKII inhibition. Moreover, ISO induces the repetitive activation of coupled RyR clusters through CaMKII activation. Immunostaining shows high levels of CaMKII phosphorylation at the dyadic cleft. CaMKII inhibition reduces ICaL and local Ca2+ transients during depolarizing steps but has only modest effects on amplitude or relaxation of the global Ca2+ transient. In contrast, protein kinase A (PKA) inhibition reduces spark frequency in all RyRs concurrently with a reduction of sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude and relaxation. In conclusion, CaMKII activation during β‐adrenergic stimulation is restricted to the dyadic cleft microdomain, enhancing LTCC‐triggered local Ca2+ release as well as spontaneous diastolic Ca2+ release whilst PKA is the major pathway increasing global Ca2+ cycling. Selective CaMKII inhibition may reduce potentially arrhythmogenic release without negative inotropy
Extracellular SPARC increases cardiomyocyte contraction during health and disease
Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and at lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury
Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release
In atrial fibrillation (AF), abnormalities in Ca(2+) release contribute to arrhythmia generation and contractile dysfunction. We explore whether RyR cluster ultrastructure is altered and is associated with functional abnormalities in AF.status: publishe
RNA-sequencing reveals that STRN, ZNF484 and WNK1 add to the value of mitochondrial MT-COI and COX10 as markers of unstable coronary artery disease
Markers in monocytes, precursors of macrophages, which are related to CAD, are largely unknown. Therefore, we aimed to identify genes in monocytes predictive of a new ischemic event in patients with CAD and/or discriminate between stable CAD and acute coronary syndrome. We included 66 patients with stable CAD, of which 24 developed a new ischemic event, and 19 patients with ACS. Circulating CD14+ monocytes were isolated with magnetic beads. RNA sequencing analysis in monocytes of patients with (n = 13) versus without (n = 11) ischemic event at follow-up and in patients with ACS (n = 12) was validated with qPCR (n = 85). MT-COI, STRN and COX10 predicted new ischemic events in CAD patients (power for separation at 1% error rate of 0.97, 0.90 and 0.77 respectively). Low MT-COI and high STRN were also related to shorter time between blood sampling and event. COX10 and ZNF484 together with MT-COI, STRN and WNK1 separated ACS completely from stable CAD patients. RNA expressions in monocytes of MT-COI, COX10, STRN, WNK1 and ZNF484 were independent of cholesterol lowering and antiplatelet treatment. They were independent of troponin T, a marker of myocardial injury. But, COX10 and ZNF484 in human plaques correlated to plaque markers of M1 macrophage polarization, reflecting vascular injury. Expression of MT-COI, COX10, STRN and WNK1, but not that of ZNF484, PBMCs paired with that in monocytes. The prospective study of relation of MT-COI, COX10, STRN, WNK1 and ZNF484 with unstable CAD is warranted
Cyclosporine A reduces microvascular obstruction and preserves left ventricular function deterioration following myocardial ischemia and reperfusion
Postconditioning and cyclosporine A prevent
mitochondrial permeability transition pore opening providing
cardioprotection during ischemia/reperfusion.
Whether microvascular obstruction is affected by these
interventions is largely unknown. Pigs subjected to coronary
occlusion for 1 h followed by 3 h of reperfusion were
assigned to control (n = 8), postconditioning (n = 9) or
cyclosporine A intravenous infusion 10-15 min before the
end of ischemia (n = 8). Postconditioning was induced by
8 cycles of repeated 30-s balloon inflation and deflation.
After 3 h of reperfusion magnetic resonance imaging,
triphenyltetrazolium chloride/Evans blue staining and histopathology
were performed. Microvascular obstruction
(MVO, percentage of gadolinium-hyperenhanced area) was
measured early (3 min) and late (12 min) after contrast
injection. Infarct size with double staining was smaller in
cyclosporine (46.2 ± 3.1 %, P = 0.016) and postconditioning
pigs (47.6 ± 3.9 %, P = 0.008) versus controls
(53.8 ± 4.1 %). Late MVO was significantly reduced by
cyclosporine (13.9 ± 9.6 %, P = 0.047) but not postconditioning
(23.6 ± 11.7 %, P = 0.66) when compared with
controls (32.0 ± 16.9 %). Myocardial blood flow in the
late MVO was improved with cyclosporine versus controls
(0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and
was inversely correlated with late-MVO extent ( = 0.93,
P\0.0001). Deterioration of left ventricular ejection
fraction (LVEF) between baseline and 3 h of reperfusion
was smaller with cyclosporine (-7.9 ± 2.4 %, P = 0.008)
but not postconditioning (-12.0 ± 5.5 %, P = 0.22) when
compared with controls (-16.4 ± 5.5 %). In the three
groups, infarct size (\beta = -0.69, P\0.001) and late MVO
(\beta = -0.33, P = 0.02) were independent predictors of
LVEF deterioration following ischemia/reperfusion
(R^{2} = 0.73, P\0.001). Despite both cyclosporine A and
postconditioning reduce infarct size, only cyclosporine A
infusion had a beneficial effect on microvascular damage
and was associated with better preserved LV function when
compared with controls
Activin A Modulates CRIPTO-1/HNF4 α
The use of human pluripotent stem cells in basic and translational cardiac research requires efficient differentiation protocols towards cardiomyocytes. In vitro differentiation yields heterogeneous populations of ventricular-, atrial-, and nodal-like cells hindering their potential applications in regenerative therapies. We described the effect of the growth factor Activin A during early human embryonic stem cell fate determination in cardiac differentiation. Addition of high levels of Activin A during embryoid body cardiac differentiation augmented the generation of endoderm derivatives, which in turn promoted cardiomyocyte differentiation. Moreover, a dose-dependent increase in the coreceptor expression of the TGF-β superfamily member CRIPTO-1 was observed in response to Activin A. We hypothesized that interactions between cells derived from meso- and endodermal lineages in embryoid bodies contributed to improved cell maturation in early stages of cardiac differentiation, improving the beating frequency and the percentage of contracting embryoid bodies. Activin A did not seem to affect the properties of cardiomyocytes at later stages of differentiation, measuring action potentials, and intracellular Ca2+ dynamics. These findings are relevant for improving our understanding on human heart development, and the proposed protocol could be further explored to obtain cardiomyocytes with functional phenotypes, similar to those observed in adult cardiac myocytes
- …