44 research outputs found
Levosimendan: Beyond its simple inotropic effect in heart failure
Classic inotropic agents provide short-term haemodynamic improvement in
patients with heart failure, but their use has been associated with poor
prognosis. A new category of inotropic agents, the Ca2+ sensitizers, may
provide an alternative longer lasting solution. Levosimendan is a
relatively new Ca2+ sensitizer which offers haemodynamic and symptomatic
improvement by combining a positive inotropic action via Ca2+
sensitization and a vasodilatory effect via adenosine
triphosphate(ATP)-sensitive K+ (K-ATP), Ca2+-activated K+ (KCa2+) and
voltage-dependent K+ (K-v) channels activation. Levosimendan also seems
to induce a prolonged haemodynamic improvement in patients with heart
failure as a result of the long half-life of its active metabolite,
OR-1896. Furthermore, there is also evidence that levosimendan may have
additional antiinflammatory and antiapoptotic properties, affecting
important pathways in the pathophysiology of heart failure. Despite the
initial reports for a clear benefit of levosimendan on short- and
long-term mortality in patients with severe heart failure, the results
from the recent clinical trials are rather disappointing, and it is
still unclear whether it is superior to dobutamine in affecting survival
of patients with severe heart failure. In conclusion, levosimendan is a
promising agent for the treatment of decompensated heart failure. As
further to its positive inotropic effect, it affects multiple pathways
with key roles in the pathophysiology of heart failure. The results of
the ongoing trials examining the effect of levosimendan on mortality in
patients with heart failure will hopefully resolve the controversy as to
whether levosimendan is superior to classic inotropic agents for the
treatment of severe heart failure. (c) 2007 Elsevier Inc. All rights
reserved
Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials
Plasma total homocysteine (Hcy) has been associated with cardiovascular
risk in multiple large-scale epidemiological studies, and it has been
considered as an independent risk factor for atherosclerosis.
Homocysteine lowering, achieved after the introduction of the folate
food fortification programme in North America, was accompanied by an
accelerated decline of cardiovascular risk and especially of stroke.
Although the initial clinical trials suggested that
homocysteine-lowering treatment with folates and B vitamins induces
coronary plaque regression, this finding was not confirmed by more
recent clinical studies. Under the light of the findings from the recent
large randomized clinical trials that failed to document a benefit of
Hcy lowering on clinical outcome of patients with atherosclerosis, the
role of Hcy as a risk factor and the efficacy of Hcy lowering against
atherosclerosis have been questioned. Therefore, better understanding of
the mechanisms relating Hcy and Hcy-lowering treatment with vascular
function and atherogenesis is crucial, to help us understand why
clinical trials failed to show a benefit from Hcy-lowering treatment.
Are these therapeutic strategies ineffective because they fail to reduce
intracellular Hcy levels and vascular redox state or should Hcy stop
being considered as an independent risk factor for atherosclerosis from
now on? In this review article, we provide a global approach of the
molecular mechanisms relating Hcy with cardiovascular risk and introduce
possible mechanistic explanations regarding the inability of clinical
trials to detect any clinical benefit from Hcy-lowering treatment in
secondary prevention. Finally, we provide clinical recommendations
regarding the therapeutic strategies targeting homocysteine in the
general population
Genetic polymorphisms of platelet glycoprotein Ia and the risk for premature myocardial infarction - Effects on the release of sCD40L during the acute phase of premature myocardial infarction
OBJECTIVES The aim of this research was to evaluate the effect of
genetic polymorphisms C807T and G1648A of platelet glycoprotein la
(GPIa), on the risk for myocardial infarction (MI) and on the release of
soluble CD40 ligand (sCD40L) during the acute phase of MI and one year
after the event.
BACKGROUND C807T and G1648A polymorphisms affect the density of GPIa on
platelet surface, but their effect on the risk for MI and the release of
sCD40L is unknown.
METHODS The study population consisted of 219 patients with premature MI
and 389 controls. One year after the event, 67 patients and 232 controls
were recalled for the follow-up study.
RESULTS The risk for MI in 807TT was 2.296 (95% confidence interval
[CI]: 1.187 to 4.440) p < 0.05 versus CC + CT, 2.269 (95% CI: 1.085
to 4.745) p < 0.05 versus CC, and 2.135 (95% CI: 1.080 to 4.219) p <
0.05 versus CT. During the acute phase of MI, sCD40L was higher in 807CT
+ TT compared with 807CC (p < 0.01), an effect persisting after one year
(p < 0.01). The carriage of 807T allele was an independent predictor for
sCD40L during the acute phase of MI (beta = 9.442 [standard error
(SE): 2.526], p = 0.001) and in the same patients one year later (beta
=8.282 [SE: 2.044], p = 0.001). In healthy individuals, 807T allele
was associated with higher sCD40L levels compared with 807CC (p < 0.05),
only among those with von Willebrand factor greater than or equal to
median.
CONCLUSIONS Genetic polymorphism C807T increases the risk for premature
MI. 807T allele is an independent predictor for sCD40L levels during the
acute phase of premature MI as well as one year after the event, while
it is associated with elevated sCD40L levels in healthy subjects, only
in the presence of high von Willebrand levels. (J Am Coll Cardiol
2006;47:1959-66) (c) 2006 by the American College of Cardiology
Foundation
Young women partition fatty acids towards ketone body production rather than VLDL-TAG synthesis, compared with young men
Before the menopause, women are relatively protected against CVD
compared with men. The reasons for this sex difference are not
completely understood, but hepatic fatty acid metabolism may play a
role. The present study aimed to investigate the utilisation of plasma
NEFA by the liver and to determine whether they are partitioned
differently into ketone bodies and VLDL-TAG in healthy, lean young men
and women. Volunteers were studied during a prolonged overnight fast
(12-19 h) using an intravenous infusion of [U-C-13] palmitate. After
12 h fasting, the women had a more advantageous metabolic profile with
lower plasma glucose (P < 0.05) and TAG (P < 0.05) but higher plasma
NEFA (P < 0.05) concentrations. Plasma 3-hydroxybutyrate (3-OHB)
concentrations rose more in women than in men, and the transfer of C-13
from [U-(13) C]palmitate to plasma [C-13]3-OHB reached a plateau 6-7
h after the start of the infusion in women but was still increasing at 6
h in men. This implies a slower 3-OHB production rate and/or dilution by
other precursor pools in men. In women, the high isotopic enrichment of
plasma 3-OHB suggested that systemic plasma fatty acids were the major
source of 3-OHB production. However, in men, this was not observed
during the course of the study(P < 0.01). There were no sex differences
for the incorporation of C-13 into VLDL1-or VLDL2-TAG. The ability of
young women to partition fatty acids towards ketone body production
rather than VLDL-TAG may contribute to their more advantageous metabolic
profile compared with young men
LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion
Summary Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. © 2015 The Authors
Novel therapies targeting vascular endothelium
Endothelial dysfunction has been identified as a major mechanism
involved in all the stages of atherogenesis. Evaluation of endothelial
function seems to have a predictive role in humans, and therapeutic
interventions improving nitric oxide bioavailability in the vasculature
may improve the long-term outcome in healthy individuals, high-risk
subjects, or patients with advanced atherosclerosis. Several therapeutic
strategies are now available, targeting both the synthesis and oxidative
inactivation of nitric oxide (NO) in human vasculature. Statins seem to
be currently the most powerful category of these agents, improving
endothelial function and decreasing cardiovascular risk after long-term
administration. Other cardiovascular agents improving endothelial
function in humans are angiotensin-converting enzyme
inhibitors/angiotensin receptors blockers, which increase NO
bioavailability by modifying the rennin-angiotensin-aldosterone system.
Newer therapeutic approaches targeting endothelial dysfunction in
specific disease states include insulin sensitizers, L-arginine (the
substrate for endothelial NO synthase [eNOS]) as well as substances
that target eNOS “coupling,” such as folates or tetrahydrobiopterin.
Although there are a variety of strategies to improve NO bioavailability
in human endothelium, it is still unclear whether they have any direct
benefit at a clinical level
Moisture Status of the Skin of the Feet Assessed by the Visual Test Neuropad Correlates With Foot Ulceration in Diabetes
OBJECTIVE - To examine the association between the moisture status of
the skin of the feet with foot ulceration in subjects with diabetes.
RESEARCH DESIGN AND METHODS - A total of 379 subjects with diabetes were
examined. Assessment of peripheral neuropathy was based on neuropathy
symptom score, neuropathy disability score, vibration perception
threshold, and the 10-g monofilament perception. The moisture status of
the skin of the feet was assessed using the visual test Neuropad.
RESULTS - Patients with foot ulceration had more severe peripheral
neuropathy and more often an abnormal Neuropad response. Multivariate
logistic regression analysis demonstrated that the odds of foot
ulceration increased with measures of neuropathy but increased also with
an abnormal Neuropad response.
CONCLUSIONS - An abnormal Neuropad response correlates with foot
ulceration in subjects with diabetes. This finding, if confirmed
prospectively, suggests that the Neuropad test may be included in the
screening tests for the prediction of foot ulceration