The effect of Crataegus oxycantha special extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure ☆

Aim To examine whether hawthorn ( Crataegus Special Extract WS 1442 {CSE}) inhibits progression in heart failure (HF) patients. Methods We performed a retrospective analysis of data from the HERB CHF study in which patients with mild to moderate HF were randomised to either CSE 900 mg or placebo for 6months. The primary outcome was time to progression of HF (HF death, hospitalisation, or sustained increase in diuretics) as assessed by log‐rank tests and by Cox modelling. Results Progression of HF occurred in 46.6% of the CSE and 43.3% of the placebo groups (OR 1.14, 95% CI=0.56, 2.35: p =0.86). Patients receiving CSE were 3.9 times (95% CI=1.1−13.7: p =0.035) more likely to experience HF progression at baseline. In adjusted analysis, the risk of having early HF progression in the CSE group increased to 6.4 (95% CI=1.5, 26.5: p =0.011). In patients with LVEF≤35%, those taking CSE were at significantly greater risk (3.2, 95% CI=1.3, 8.3: p =0.02) than the placebo group. Conclusions CSE does not reduce heart failure progression in patients who have HF. CSE appears to increase the early risk of HF progression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102656/1/ejhf2008-04-008.pd

Stumbling Reactions in Partial Gravity – Neuromechanics of Compensatory Postural Responses and Inter-Limb Coordination During Perturbation of Human Stance

Spontaneous changes in gravity play a significant role in interplanetary space missions. To preserve the astronauts’ capability to execute mission-critical tasks and reduce the risk of injury in transit and on planetary surfaces, a comprehensive understanding of the neuromuscular control of postural responses after balance deterioration in hypo- or hyper-gravity conditions is essential. Therefore, this study aimed to evaluate the effect of acute gravitational variation on postural adjustments in response to perturbations. Gravitational changes were induced using parabolic flight. Postural set was manipulated by randomly providing unilateral left, bilateral or split perturbations which require balance corrections to restore postural stability. In six subjects, postural reactions were recorded after anterior and posterior surface perturbations for progressively increased gravitational conditions spanning from 0.25 to 1.75 g. Ankle and knee joint kinematics and electromyograms (EMG) of eight leg muscles were recorded prior (PRE) and after perturbation onset. Muscle activation onset latencies and amplitudes in the short-, medium-, and long-latency responses (SLR, MLR, LLR) were assessed. Results demonstrate an increased muscle activity (p < 0.05) and co-contraction in the lower extremities (p < 0.05) prior to perturbation in hypo- and hyper-gravity. After perturbation, reduced muscle onset latencies (p < 0.05) and increased muscle activations in the MLR and LLR (p < 0.05), concomitant with an increased co-contraction in the SLR, were manifested with a progressive rise in gravity. Ankle and knee joint deflections remained unaffected, whereas angular velocities increased (p < 0.05) with increasing gravitation. Effects were more pronounced in bi- compared to unilateral or split perturbations (p < 0.05). Neuro-mechanical adaptations to gravity were more distinct and muscle onset latencies were shorter in the displaced compared to the non-displaced leg. In conclusion, the timing and magnitude of postural reflexes involved in stabilization of bipedal stance are gravity-dependent. The approximately linear relationship between gravity and impulse-directed EMG amplitudes or muscle onset latencies after perturbation indicates that the central nervous system correctly predicts the level of gravity. Moreover, it accurately governs contractions in the antigravity musculature to counterbalance the gravitational pull and to regain upright posture after its disturbance. Importantly, unilateral perturbations evoked fast reflex responses in the synergistic muscles of the non-displaced contralateral leg suggesting a synchronized inter-limb coordination mediated by spinal circuitries

Hotline update of clinical trials and registries presented at the American College of Cardiology Congress 2010: ACCORD, INVEST, NAVIGATOR, RACE II, SORT OUT III, CSP-474, DOSE, ASPIRE and more

This article gives an overview on a number of novel clinical trials in the field of cardiovascular medicine, which were presented during the Late Breaking Clinical Trial Sessions at the 59th annual meeting of the American College of Cardiology in Atlanta, USA, from 14th March to 16th March 2010. The data were presented by leading experts in the field with relevant positions in the trials. These comprehensive summaries should provide the readers with the most recent data on diagnostic and therapeutic developments in cardiovascular medicine similar as previously reported (Schirmer SH, van der Laan AM, Bohm M, Mahfoud F in Clin Res Cardiol 98:691–699, 2009; Maier LS, Schirmer SH, Walenta K, Jacobshagen C, Bohm M in Clin Res Cardiol 98:413–419, 2009)

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Many conditions culminate in heart failure (HF), a multi-organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence-base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite

Angiographic Findings of the Multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL)

BACKGROUND: Restenosis remains the major limitation of coronary catheter-based intervention. In small vessels, the amount of neointimal tissue is disproportionately greater than the vessel caliber, resulting in higher restenosis rates. In the Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL) trial, approximately 40% of the vessels were small (<2.5 mm). The present study evaluates the relationship between angiographic outcome and vessel diameter for sirolimus-eluting stents. METHODS AND RESULTS: Patients were randomized to receive either an 18-mm bare metal Bx VELOCITY (BS group, n=118), or a sirolimus-eluting Bx VELOCITY stent (SES group, n=120). Subgroups were stratified into tertiles according to their reference diameter (RD; stratum I, RD 2.84 mm). At 6-month follow-up, the restenosis rate in the SES group was 0% in all strata (versus 35%, 26%, and 20%, respectively, in the BS group). In-stent late loss was 0.01+/-0.25 versus 0.80+/-0.43 mm in stratum I, 0.01+/-0.38 versus 0.88+/-0.57 mm in stratum II, and -0.06+/-0.35 versus 0.74+/-0.57 mm in stratum III (SES versus BS). In SES, the minimal lumen diameter (MLD) remained unchanged (Delta -0.72 to 0.72 mm) in 97% of the lesions and increased (=late gain, DeltaMLD <-0.72 mm) in 3% of the lesions. Multivariate predictors for late loss were treatment allocation (P<0.001) and postprocedural MLD (P= 0.008). CONCLUSIONS: Sirolimus-eluting stents prevent neointimal proliferation and late lumen loss irrespective of the vessel diameter. The classic inverse relationship between vessel diameter and restenosis rate was seen in the bare stent group but not in the sirolimus-eluting stent group

Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and a leading cause of neurological disability. The complex immunopathology and variable disease course of multiple sclerosis have limited effective treatment of all patients. Altering the metabolism of immune cells may be an attractive strategy to modify their function during autoimmunity. We examined the effect of inhibiting fatty acid metabolism in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Mice treated with an inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme in the beta-oxidation of fatty acids, showed a reduction in disease severity as well as less inflammation and demyelination. Inhibition of CPT-1 in encephalitogenic T-cells resulted in increased apoptosis and reduced inflammatory cytokine production. These results suggest that disruption of fatty acid metabolism promotes downregulation of inflammation in the CNS and that this metabolic pathway is a potential therapeutic target for multiple sclerosis

Effect of Muscle Length on Cross-Bridge Kinetics in Intact Cardiac Trabeculae at Body Temperature

Dynamic force generation in cardiac muscle, which determines cardiac pumping activity, depends on both the number of sarcomeric cross-bridges and on their cycling kinetics. The Frank–Starling mechanism dictates that cardiac force development increases with increasing cardiac muscle length (corresponding to increased ventricular volume). It is, however, unclear to what extent this increase in cardiac muscle length affects the rate of cross-bridge cycling. Previous studies using permeabilized cardiac preparations, sub-physiological temperatures, or both have obtained conflicting results. Here, we developed a protocol that allowed us to reliably and reproducibly measure the rate of tension redevelopment (ktr; which depends on the rate of cross-bridge cycling) in intact trabeculae at body temperature. Using K+ contractures to induce a tonic level of force, we showed the ktr was slower in rabbit muscle (which contains predominantly β myosin) than in rat muscle (which contains predominantly α myosin). Analyses of ktr in rat muscle at optimal length (Lopt) and 90% of optimal length (L90) revealed that ktr was significantly slower at Lopt (27.7 ± 3.3 and 27.8 ± 3.0 s−1 in duplicate analyses) than at L90 (45.1 ± 7.6 and 47.5 ± 9.2 s−1). We therefore show that ktr can be measured in intact rat and rabbit cardiac trabeculae, and that the ktr decreases when muscles are stretched to their optimal length under near-physiological conditions, indicating that the Frank–Starling mechanism not only increases force but also affects cross-bridge cycling kinetics

Nanomechanics and Sodium Permeability of Endothelial Surface Layer Modulated by Hawthorn Extract WS 1442

The endothelial glycocalyx (eGC) plays a pivotal role in the physiology of the vasculature. By binding plasma proteins, the eGC forms the endothelial surface layer (ESL) which acts as an interface between bloodstream and endothelial cell surface. The functions of the eGC include mechanosensing of blood flow induced shear stress and thus flow dependent vasodilation. There are indications that levels of plasma sodium concentrations in the upper range of normal and beyond impair flow dependent regulation of blood pressure and may therefore increase the risk for hypertension. Substances, therefore, that prevent sodium induced endothelial dysfunction may be attractive for the treatment of cardiovascular disease. By means of combined atomic force - epifluorescence microscopy we studied the impact of the hawthorn (Crataegus spp.) extract WS 1442, a herbal therapeutic with unknown mechanism of action, on the mechanics of the ESL of ex vivo murine aortae. Furthermore, we measured the impact of WS 1442 on the sodium permeability of endothelial EA.hy 926 cell monolayer. The data show that (i) the ESL contributes by about 11% to the total endothelial barrier resistance for sodium and (ii) WS 1442 strengthens the ESL resistance for sodium up to about 45%. This mechanism may explain some of the vasoprotective actions of this herbal therapeutic