Weak transcranial direct current stimulation (tDCS) with a homogenous DC field at intensities of around 1 mA induces long-lasting changes in the brain. tDCS can be used to manipulate brain ...excitability via membrane polarisation: cathodal stimulation hyperpolarises, while anodal stimulation depolarises the resting membrane potential, whereby the induced after-effects depend on polarity, duration and intensity of the stimulation. A variety of other parameters influence tDCS effects; co-application of neuropharmacologically active drugs may most impressively prolong or even reverse stimulation effects. Transcranial alternating stimulation (tACS) and random noise stimulation (tRNS) are used to interfere with ongoing neuronal oscillations and also finally produce neuroplastic effects if applied with appropriate parameters.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A ...new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.
There are two established causes of high diastolic left ventricular stiffness: fibrosis and the rigidification of titin. A recent scientific study of a mouse model points to a third path, with ...implications for new experimental strategies.
In accordance with the comorbidity-inflammation paradigm, comorbidities and especially metabolic comorbidities are presumed to drive development and severity of heart failure with preserved ejection ...fraction through a cascade of events ranging from systemic inflammation to myocardial fibrosis. Recently, novel experimental and clinical evidence emerged, which strengthens the validity of the inflammatory/profibrotic paradigm. This evidence consists among others of (1) myocardial infiltration by immunocompetent cells not only because of an obesity-induced metabolic load but also because of an arterial hypertension-induced hemodynamic load. The latter is sensed by components of the extracellular matrix like basal laminin, which also interact with cardiomyocyte titin; (2) expression in cardiomyocytes of inducible nitric oxide synthase because of circulating proinflammatory cytokines. This results in myocardial accumulation of degraded proteins because of a failing unfolded protein response; (3) definition by machine learning algorithms of phenogroups of patients with heart failure with preserved ejection fraction with a distinct inflammatory/profibrotic signature; (4) direct coupling in mediation analysis between comorbidities, inflammatory biomarkers, and deranged myocardial structure/function with endothelial expression of adhesion molecules already apparent in early preclinical heart failure with preserved ejection fraction (HF stage A, B). This new evidence paves the road for future heart failure with preserved ejection fraction treatments such as biologicals directed against inflammatory cytokines, stimulation of protein ubiquitylation with phosphodiesterase 1 inhibitors, correction of titin stiffness through natriuretic peptide-particulate guanylyl cyclase-PDE9 (phosphodiesterase 9) signaling and molecular/cellular regulatory mechanisms that control myocardial fibrosis.
Aortic stenosis Carabello, Blase A, Prof; Paulus, Walter J, Prof
The Lancet (British edition),
03/2009, Letnik:
373, Številka:
9667
Journal Article
Recenzirano
Summary In developed countries, aortic stenosis is the most prevalent of all valvular heart diseases. A manifestation of ageing, the disorder is becoming more frequent as the average age of the ...population increases. Symptomatic severe disease is universally fatal if left untreated yet is consistent with a typical lifespan when mechanical relief of the stenosis is provided in a timely fashion. Management of mild disease, severe asymptomatic disease, and far advanced disease, and the effect of new percutaneous treatments, provide both controversy and exciting promise to care of patients with aortic stenosis. We discuss these issues in this Review.
Transcranial direct current stimulation (tDCS) causes a complex spatial distribution of the electric current flow in the head which hampers the accurate localization of the stimulated brain areas. In ...this study we show how various anatomical features systematically shape the electric field distribution in the brain during tDCS. We constructed anatomically realistic finite element (FEM) models of two individual heads including conductivity anisotropy and different skull layers. We simulated a widely employed electrode montage to induce motor cortex plasticity and moved the stimulating electrode over the motor cortex in small steps to examine the resulting changes of the electric field distribution in the underlying cortex. We examined the effect of skull thickness and composition on the passing currents showing that thinner skull regions lead to higher electric field strengths. This effect is counteracted by a larger proportion of higher conducting spongy bone in thicker regions leading to a more homogenous current over the skull. Using a multiple regression model we could identify key factors that determine the field distribution to a significant extent, namely the thicknesses of the cerebrospinal fluid and the skull, the gyral depth and the distance to the anode and cathode. These factors account for up to 50% of the spatial variation of the electric field strength. Further, we demonstrate that individual anatomical factors can lead to stimulation "hotspots" which are partly resistant to electrode positioning. Our results give valuable novel insights in the biophysical foundation of tDCS and highlight the importance to account for individual anatomical factors when choosing an electrode montage.
Diabetes mellitus-related cardiomyopathy (DMCMP) was originally described as a dilated phenotype with eccentric left ventricular (LV) remodelling and systolic LV dysfunction. Recently however, ...clinical studies on DMCMP mainly describe a restrictive phenotype with concentric LV remodelling and diastolic LV dysfunction. Both phenotypes are not successive stages of DMCMP but evolve independently to respectively heart failure with preserved left ventricular ejection fraction (HFPEF) or reduced left ventricular ejection fraction (HFREF). Phenotype-specific pathophysiological mechanisms were recently proposed for LV remodelling and dysfunction in HFPEF and HFREF consisting of coronary microvascular endothelial dysfunction in HFPEF and cardiomyocyte cell death in HFREF. A similar preferential involvement of endothelial or cardiomyocyte cell compartments explains DMCMP development into distinct restrictive/HFPEF or dilated/HFREF phenotypes. Diabetes mellitus (DM)-related metabolic derangements such as hyperglycaemia, lipotoxicity, and hyperinsulinaemia favour development of DMCMP with restrictive/HFPEF phenotype, which is more prevalent in obese type 2 DM patients. In contrast, autoimmunity predisposes to a dilated/HFREF phenotype, which manifests itself more in autoimmune-prone type 1 DM patients. Finally, coronary microvascular rarefaction and advanced glycation end-products deposition are relevant to both phenotypes. Diagnosis of DMCMP requires impaired glucose metabolism and exclusion of coronary, valvular, hypertensive, or congenital heart disease and of viral, toxic, familial, or infiltrative cardiomyopathy. In addition, diagnosis of DMCMP with restrictive/HFPEF phenotype requires normal systolic LV function and diastolic LV dysfunction, whereas diagnosis of DMCMP with dilated/HFREF phenotype requires systolic LV dysfunction. Treatment of DMCMP with restrictive/HFPEF phenotype is limited to diuretics and lifestyle modification, whereas DMCMP with dilated/HFREF phenotype is treated in accordance to HF guidelines.
Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced ...EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.
PDF
