J. Farré

Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study.

OBJECTIVES This multicenter study sought to evaluate the long-term follow-up of patients ablated for idiopathic ventricular fibrillation (VF). BACKGROUND Catheter ablation of idiopathic VF that targets ventricular premature beat (VPB) triggers has been shown to prevent VF recurrences on short-term follow-up. METHODS From January 2000, 38 consecutive patients from 6 different centers underwent ablation of primary idiopathic VF initiated by short coupled VPB. All patients had experienced at least 1 documented VF, with 87% having experienced > or =2 VF episodes in the preceding year. Catheter ablation was guided by activation mapping of VPBs or pace mapping during sinus rhythm. RESULTS There were 38 patients (21 men) age 42 +/- 13 years, refractory to a median of 2 antiarrhythmic drugs. Triggering VPBs originated from the right (n = 16), the left (n = 14), or both (n = 3) Purkinje systems and from the myocardium (n = 5). During a median post-procedural follow-up of 63 months, 7 (18%) of 38 patients experienced VF recurrence at a median of 4 months. Five of these 7 patients underwent repeat ablation without VF recurrence. Survival free of VF was predicted only by transient bundle-branch block in the originating ventricle during the electrophysiological study (p < 0.0001). The number of significant events (confirmed VF or aborted sudden death) was reduced from 4 (interquartile range 3 to 9) before to 0 (interquartile range 0 to 4) after ablation (p = 0.01). CONCLUSIONS Ablation for idiopathic VF that targets short coupled VPB triggers is associated with a long-term freedom from VF recurrence.

Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor‐α release by cultured smooth muscle cells

Inflammatory related cardiovascular disease, i.e. cardiac allograft rejection, myocarditis, septic shock, are accompanied by cytokine production, which stimulates the expression of inducible nitric oxide (iNOS).

Expression of Inducible Nitric Oxide Synthase After Endothelial Denudation of the Rat Carotid Artery Role of Platelets

There is functional evidence suggesting that endothelial denudation stimulates inducible nitric oxide synthase (iNOS) activity in the vascular wall. In vitro studies have shown that iNOS expression in smooth muscle cells is reduced by endothelial cells. In the present study we have analyzed the time course of iNOS protein expression in the arterial wall after in vivo deendothelialization. Endothelial denudation was performed in the left carotid artery of Wistar rats, and the right carotid artery was used as control. Whereas iNOS protein was weakly expressed 6, 24, and 48 hours after endothelial denudation, a marked iNOS expression was found 7, 14, and 30 days after vascular damage. Because platelet adhesion and aggregation occur early after endothelial damage, we studied the role of activated platelets in the negative modulation of iNOS protein expression during the first 2 days after endothelial denudation. Early after in vivo endothelial injury, platelet-depleted rats showed a marked iNOS protein expression in the vascular wall. Similar results were obtained by blocking the platelet glycoprotein (GP) IIb/IIIa. Although iNOS protein is present in the arterial wall several days after endothelial denudation, early after arterial wall injury iNOS protein is weakly expressed. Platelets play a crucial role in preventing iNOS protein expression early after endothelial damage, an effect that can be avoided with GP IIb/IIIa blockers. Although iNOS protein was weakly expressed in vivo in the rat carotid artery wall 6, 24, and 48 hours after balloon endothelial denudation, a marked iNOS expression was found 7, 14, and 30 days after arterial damage. iNOS expression could be increased early after endothelial injury by removing circulating platelets and by an antibody against the GP IIb/IIIa. In conclusion, platelets prevent iNOS protein expression early after endothelial balloon damage, an effect that can be avoided with GP IIb/IIIa blocking agents.

Prior aspirin use in unstable angina patients with modified plasma inflammatory markers and endothelial nitric oxide synthase in neutrophils

Background  Prior use of aspirin in patients with acute coronary syndrome has been associated with a lower incidence of acute myocardial infarction. The aim of this study was to explore if prior aspirin therapy in unstable angina (UA) patients could modify systemic inflammatory markers such as interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and intercellular adhesion molecule‐1 (ICAM‐1) and the expression of endothelial nitric oxide synthase (eNOS) in neutrophils.

Estrogen stimulates neuronal nitric oxide synthase protein expression in human neutrophils

Recent studies have postulated the contribution of nitric oxide (NO) released by the endothelium to the beneficial effects of estrogen. Despite a neuronal-type NO synthase (nNOS) described in neutrophils, less is known about the effect of estrogen in these cells. The aim of the present study was to analyze the expression of nNOS protein in human neutrophils under different estrogenic conditions. We first analyzed nNOS expression in neutrophils obtained from premenopausal women. During the first 2 days of the follicular phase (low circulating estrogen concentrations), nNOS expression in neutrophils was reduced with respect to that found in neutrophils obtained from the same donors during the ovulatory phase (high circulating estrogen concentrations). Moreover, the expression of nNOS protein in neutrophils obtained from postmenopausal women after transdermal estrogen therapy was markedly enhanced with respect to that observed before the treatment. In vitro incubation of neutrophils derived from men for 6 hours with 17beta-estradiol (10(-10) to 10(-8) mol/L) upregulated the expression of nNOS protein. The 17beta-estradiol receptor antagonists, tamoxifen (10(-8) mol/L) and ICI 182780 (10(-8) mol/L), inhibited the upregulation of nNOS protein induced by 17beta-estradiol. The putative functional implication was denoted by a reduced expression of the CD18 antigen on the surface of 17beta-estradiol-incubated neutrophils, which was accompanied by a decreased adhesive capacity. Both effects were prevented by an NO antagonist. In conclusion, the in vivo levels of circulating estrogen concentrations seem to be associated with the level of nNOS protein expression in neutrophils from women. Moreover, low doses of 17beta-estradiol upregulate nNOS protein expression in neutrophils from men. The increased ability of 17beta-estradiol-incubated neutrophils derived from men to produce NO reduced their adhesive properties.

Doxazosin modifies Bcl-2 and Bax protein expression in the left ventricle of spontaneously hypertensive rats

Background Increased apoptosis has recently been reported in the heart of spontaneously hypertensive rats (SHRs). Objective To investigate the molecular basis of apoptosis in the left ventricle of SHRs in terms of the expression of Bcl-2 protein (which protects from apoptosis) and Bax protein (which acts as an apoptotic promoter). In addition, we analysed the involvement of α1-adrenergic receptors in the left ventricular apoptosis of SHRs. Methods The study was performed in untreated SHRs (n = 16) and SHRs that were orally treated with doxazosin (10 mg/kg body weight per day, for 15 days), a selective α1-receptor blocker (n = 16). A group of Wistar–Kyoto (WKY) rats (n = 16) was used as the control. Results The left ventricles of untreated SHRs showed a significant increase in Bcl-2 protein expression and a reduced presence of Bax protein. The ratio of Bcl-2:Bax in SHRs was higher than in WKY rats, suggesting an anti-apoptotic state. Paradoxically, both the number of apoptotic cardiac cells and the cleavage of an 85-kDa fragment of the poly (ADP-ribose) polymerase (PARP), a marker of caspase-3 activity, were higher in the left ventricle of SHRs than in WKY rats, suggesting an apoptotic situation. Bax promotes cell apoptosis when it is bound to Bcl-2. We then determined the abundance of Bax–Bcl-2 complexes in the left ventricle of the two groups of animals. Bax–Bcl-2 complexes were more abundant in SHRs than WKY rats. In a second set of experiments, we analysed the role of α1-adrenergic blockade by doxazosin in the above-described mechanisms. Doxazosin treatment reduced the formation of Bax–Bcl-2 complexes in the left ventricle of SHRs, and this was accompanied by a decrease in the levels of 85-kDa PARP and a reduction in apoptotic left ventricular cells. Conclusions The present work suggests that the presence of Bax–Bcl-2 complexes in the left ventricle could be a more reliable marker of the apoptotic state than the determination of the absolute expression of Bcl-2 and Bax proteins. Moreover, the inhibition of α1-adrenergic receptors by doxazosin decreased the abundance of Bax–Bcl-2 complexes and promoted a reduction of apoptosis in the left ventricle of SHRs.