7 research outputs found
[Heart failure: an endothelial disorder?]
Scompenso cardiac
Neurohormones, cytokines and programmed cell death in heart failure: a new paradigm for the remodeling heart.
Irrespective of the causes or the clinical manifestations
of chronic heart failure (CHF), or even the criteria used
to define it, one fact of the syndrome is irrefutable:CHF
is a progressive disease, carries a poor long term prognosis
and mortality rates remain high despite all the
currently available therapy [1,2].
There is a general acceptance that, as heart disease
progresses into CHF, cardiac function further deteriorates
and symptoms become manifest. Although
researches produce an ever-changing picture of the syndrome,
it is now clear that CHF can no longer be considered
a contractile disorder or a disease of the heart
alone. Clinical manifestations are the result of changes
to the heart’s cellular and molecular components and to
the mediators that drive homeostatic control, particularly
(i.e. neurohormones and cytokines). Clinical data
indicate that therapeutic intervention aimed solely at
correcting hemodynamic abnormalities (i.e. those offering
symptomatic relief or improved hemodynamics)
do not necessarily slow heart failure progression
or reduce mortality [1–3]. On the contrary, interventions
modulating the neurohormonal activation (i.e.
angiotensin converting enzyme (ACE) inhibition, betablockade
and anti-aldosterone therapy) are known to
slow progression of the syndrome and to reduce morbidity
and mortality [1,2,4–7].
From a pure clinical perspective, progression of the
disease is not detectable, particularly if not immediately
associated to symptoms deterioration. There is,
however, general acceptance that as heart failure progresses,
the shape of the heart changes, its size increases
and cardiac function deteriorates. Although
different terms have been used to describe it, cardiac
remodeling encompassesmanychanges associated with
progressive heart failure. Thus, cardiac remodeling is
recognised as an important aspect of cardiovascular
disease progression and is, therefore, emerging as a
therapeutic target in CHF of all aetiologies.
Currently, the origin of cardiac remodeling is
thought to be multifactorial and remains unknown. A
complex interaction between myocyte hypertrophy and
apoptopic death finally leading to the reshaping of the
left ventricle is believed to be of great importance.
The triggers for such a mitotic and anti-mitotic behaviour
are discussed. Since neurohormones and cytokines
can both enhance cell proliferation and death,
they constitute an interesting field of investigation in
respect to this. This paper provides an overview of
key concepts about cardiac remodeling, especially focusing
on the role that neurohormones and cytokines
are thought to play through cell hypertrophy and
apoptosis
Aorta and skeletal muscle NO synthase expression in experimental heart failure.
Nitric oxide (NO), the free radical that accounts for the biological activity of endothelium-derived relaxing factor, is synthesized from L-arginine by NO synthase (NOS). There is evidence that NO availability is reduced in the peripheral vasculature of patients with congestive heart failure (CHF). The aim of this study was to investigate the expression of NOS in the descending aorta and in the skeletal muscles of rats subjected to heart failure. The alkaloid, monocrotaline, was used to induce pulmonary hypertension and cardiac failure in rats. The expression of both the constitutive (ecNOS) and the inducible (iNOS) isoforms of the enzyme was assessed by Western blot analysis. In CHF animals, the ecNOS location in the aorta is altered: the endothelial protein expression is substantially reduced (from 0.083 +/- 0.012 to 0.003 +/- 0.004 OD/microgram total proteins, P < 0.001) whereas the expression of ecNOS in the smooth muscle is increased (from 0.024 +/- 0.004 to 0.059 +/- 0.009 OD/ microgram total proteins, P < 0.01). The total aortic ecNOS is diminished in CHF respect to control animals (0.062 +/- 0.009 v 0.107 +/- 0.013 OD/microgram total proteins, P < 0.01). On the contrary, no difference in ecNOS protein expression was observed in the extensor digitorum longus and soleus muscles. Furthermore, iNOS was not detected in any of the tissues considered. In conclusion, experimental CHF causes a re-setting of the ecNOS protein expression in the descending aorta but not in skeletal muscles. The reduced abundance of ecNOS in the aortic endothelium is consistent with the impairment of the vasodilating function reported in patients with CHF
Oxidative stress during myocardial ischaemia and heart failure.
Oxidative stress is a condition in which oxidant metabolites exert toxic effects because of their increased production or an altered cellular mechanism of protection. The heart needs oxygen but it is also susceptible to oxidative stress, which occurs during post-ischaemic reperfusion, for example. Ischaemia causes alterations in the defence mechanisms against oxygen free radicals. At the same time, production of oxygen free radicals increases. In man, there is evidence of oxidative stress during surgical reperfusion of the whole heart, or after thrombolysis, and it is related to transient left ventricular dysfunction or stunning. At present, there are few data on oxidative stress in the failing heart. It is not clear whether the defence mechanisms of the myocyte are altered or whether the production of oxygen free radicals is increased, or both. Recent data have shown a close link between oxidative stress and apoptosis. Importantly, tumour necrosis factor causes a rapid rise in intracellular reactive oxygen intermediates and apoptosis. This series of events is not confined to the myocytes, but also occurs at the level of endothelium, where tumour necrosis factor causes expression of inducible nitric oxide synthase, production of the reactive radical nitric oxide, oxidative stress and apoptosis. The immunological response to heart failure may result in endothelial and myocyte dysfunction through oxidative stress-mediated apoptosis. A better understanding of these mechanisms may lead to novel therapeutic strategies
Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-alpha.
AIMS: We studied the induction of monocytic inducible nitric oxide synthase expression and the tumour necrosis factor-alpha system in patients with congestive heart failure. METHODS AND RESULTS: Forty-three congestive heart failure patients and 15 healthy subjects were studied. Antigenic tumour necrosis factor-alpha and its soluble receptors, measured by ELISA, were increased in chronic heart failure and the increase was related to the clinical severity of the syndrome (tumour necrosis factor-alpha from 8.2+/-5.2 in NYHA class II to 18.2+/-7.2 in class III and 26.9+/-13.2 pg. ml(-1)in class IV, P<0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor I from 1.0+/-0.2 in class II to 2.3+/-1.1 in class III and 5.5+/-3.2 ng. ml(-1)in class IV, P<0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor II from 2.7+/-0.7 in class II to 4.9+/-1.9 in class III and 8.4+/-5.0 ng. ml(-1)in class IV, P<0.002 classes III and IV vs class II). Monocytic inducible nitric oxide synthase assessed by Western blot, was expressed only in congestive heart failure patients (13 out of 43). The association among monocytic inducible nitric oxide synthase expression, tumour necrosis factor-alpha system activation, neurohormones and other clinical parameters was studied. The univariate logistic regression showed that inducible nitric oxide synthase expression was strictly associated with NYHA class (P<0.05), antigenic tumour necrosis factor-alpha (P<0.01) and its soluble receptors (P<0.05). The multivariate analysis showed that antigenic tumour necrosis factor-alpha was the only predictor for monocytic inducible nitric oxide synthase expression (P<0.05, RR=2.75, CI 1. 34-5.43). CONCLUSIONS: Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system