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Biomedical subjects

Massimo Chiariello

Publications and source records attributed to Massimo Chiariello.

At least 19 recordsLinked to original sources
PubMed2006

Relationship between oxidative stress, lipid peroxidation, and ultrastructural damage in patients with coronary artery disease undergoing cardioplegic arrest/reperfusion.

OBJECTIVE: In animal models, formation of oxidants during postischemic reperfusion may exert deleterious effects ("oxidative stress"). Cardioplegic arrest/reperfusion during cardiac surgery might similarly induce oxidative stress. However, the phenomenon has not been precisely characterized in patients, and therefore the role of antioxidant therapy at cardiac surgery is a matter of debate. Thus, we wanted to ascertain whether the relationship between oxidant formation and development of myocardial injury also translates to the situation of patients subjected to cardioplegic arrest. METHODS: In 24 patients undergoing coronary artery bypass, trans-cardiac blood samples and myocardial biopsies were taken before cardioplegic arrest and again following reperfusion. RESULTS: Cardiac glutathione release (marker of oxidant production) was negligible at baseline (0.02+/-0.04 micromol/L), but it increased 15 min into reperfusion (1.10+/-0.40 micromol/L; p<0.05); concomitantly, myocardial concentration of the antioxidant ubiquinol decreased from 144.5+/-52.0 to 97.6+/-82.0 nmol/g (p<0.05). Although these changes document cardiac exposure to oxidants, they were not accompanied by evidence of injury. Neither coronary sinus blood nor cardiac biopsies showed increased lipid peroxide concentrations. Furthermore, electron microscopy showed no major ultrastructural alterations. Finally, full recovery of left ventricular systolic and diastolic function was observed. CONCLUSIONS: Careful investigation reveals that while oxidant production does occur during cardiac surgery in patients with chronic ischemic heart disease, cardiac oxidative stress may not progress through membrane damage and irreversible injury.

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PubMed2006

Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention.

BACKGROUND: Despite its limitations, unfractionated heparin has been the standard anticoagulant used during percutaneous coronary intervention (PCI). Several small studies have suggested that intravenous enoxaparin may be a safe and effective alternative. Our primary aim was to assess the safety of enoxaparin as compared with that of unfractionated heparin in elective PCI. METHODS: In this prospective, open-label, multicenter, randomized trial, we randomly assigned 3528 patients with PCI to receive enoxaparin (0.5 or 0.75 mg per kilogram of body weight) or unfractionated heparin adjusted for activated clotting time, stratified according to the use or nonuse of glycoprotein IIb/IIIa inhibitors. The primary end point was the incidence of major or minor bleeding that was not related to coronary-artery bypass grafting. The main secondary end point was the percentage of patients in whom the target anticoagulation levels were reached. RESULTS: Enoxaparin at a dose of 0.5 mg per kilogram was associated with a significant reduction in the rate of non-CABG-related bleeding in the first 48 hours, as compared with unfractionated heparin (5.9% vs. 8.5%; absolute difference, -2.6; 95% confidence interval [CI], -4.7 to -0.6; P=0.01), but the higher enoxaparin dose was not (6.5% vs. 8.5%; absolute difference, -2.0; 95% CI, -4.0 to 0.0; P=0.051). The incidence of major bleeding was significantly reduced in both enoxaparin groups, as compared with the unfractionated heparin group. Target anticoagulation levels were reached in significantly more patients who received enoxaparin (0.5-mg-per-kilogram dose, 79%; 0.75-mg-per-kilogram dose, 92%) than who received unfractionated heparin (20%, P<0.001). CONCLUSIONS: In elective PCI, a single intravenous bolus of 0.5 mg of enoxaparin per kilogram is associated with reduced rates of bleeding, and a dose of 0.75 mg per kilogram yields rates similar to those for unfractionated heparin, with more predictable anticoagulation levels. The trial was not large enough to provide a definitive comparison of efficacy in the prevention of ischemic events. (ClinicalTrials.gov number, NCT00077844 [ClinicalTrials.gov].).

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PubMed2006

Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize beta-adrenergic receptor function in heart failure.

Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Normalization of betaAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that betaAR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of betaARs by betaAR kinase 1 (betaARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that betaARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of betaARK1 to the plasma membrane also promotes the betaAR-targeting of PI3Ks. At the plasma membrane, the generation of 3'-phosphorylated phosphatidylinositols by PI3K is required in the process of endocytosis, a prodrome to receptor downregulation. A large body of data now indicates that betaAR-targeting of PI3Ks is consistently associated with abnormalities of betaAR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of betaAR-targeted PI3K activity and novel experimental strategies to disrupt the betaARK1/PI3K complex and in turn ameliorate betaAR dysfunction and the progression of heart failure.

Adrenergic beta-Agonists↗
PubMed2006

Metabolic syndrome in peripheral arterial disease: relationship with severity of peripheral circulatory insufficiency, inflammatory status, and cardiovascular comorbidity.

OBJECTIVE: Metabolic syndrome is defined by the clustering in the same person of at least three risk factors such as hyperglycemia, hypertriglyceridemia, low levels of high-density lipoprotein, hypertension, and abdominal obesity. In patients with peripheral arterial disease (PAD), we investigated the prevalence of metabolic syndrome and its relationship with the severity of peripheral circulatory insufficiency, inflammatory status, and cardiovascular comorbidity. METHODS: The presence of metabolic syndrome was assessed in 154 consecutive PAD patients (115 men, 39 women). Inflammatory status was assessed by measuring serum levels of C-reactive protein (CRP). RESULTS: Metabolic syndrome was present in 51.9% (42.7 % in men, 74.3% in women, P < .01). Patients with an ankle/brachial index (ABI) <0.64 (median) were more likely to have metabolic syndrome than those with less severe PAD (63.9% vs 42.8%, P < .02). The association between a low ABI and metabolic syndrome was maintained after adjustment for age and sex (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.03 to 4.68). Compared with PAD patients without metabolic syndrome, those with the syndrome had greater body mass index (28.2 [25.6; 29.8] kg/m(2) vs 26.1 [24.2; 27.7] kg/m(2), P < .01) and higher levels of CRP (3.9 [1.6; 7.6] mg/L vs 2.0 [1.1; 3.7] mg/L, P < .02). A previous myocardial infarction was documented in 58.2% of patients with and in 37.5% of those without metabolic syndrome (P < .01). At multivariate analysis, metabolic syndrome was significantly associated with previous myocardial infarction also after adjustment for ABI (OR, 2.15; 95% CI, 1.06 to 4.38). CONCLUSIONS: Metabolic syndrome is present in >50% of PAD patients. The finding that well-established indicators of increased cardiovascular risk such as low ABI and increased CRP levels cluster with metabolic syndrome suggests that identification of this syndrome in these high-risk patients could indicate an even greater risk of cardiovascular events.

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PubMed2006

Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism.

BACKGROUND: Recent studies indicate that T-cell activation may play an important role in the pathophysiology of acute coronary syndromes (ACS). However, although those studies detected T-cell expansion in peripheral blood cells, demonstration of specific T-cell expansion within the plaque of patients with ACS is lacking. The present study aims to address whether a specific, immune-driven T-lymphocyte recruitment occurs within the unstable plaque of patients with ACS. METHODS AND RESULTS: We simultaneously examined the T-cell repertoire using CDR3 size analysis both in coronary plaques (obtained by directional atherectomy) and in peripheral blood of patients with either ACS (n=11) or chronic stable angina (n=10). Unstable plaques showed a 10-fold increase in T-cell content by quantitative PCR. Using spectratyping analysis, we found several specific T-cell clonotype expansions only in unstable plaque from each patient with ACS, indicating a specific, antigen-driven recruitment of T cells within unstable lesions. CONCLUSIONS: For the first time, T-cell repertoire was investigated directly into coronary plaques; using this approach, we demonstrate that coronary plaque instability in the setting of ACS is associated with immune-driven T-cell recruitment, specifically within the plaque.

Acute Disease↗
PubMed2006

Cellular adhesion molecules and peripheral arterial disease.

Cellular adhesion molecules (CAMs), by mediating the recruitment of circulating leukocytes to the blood vessel wall and their subsequent migration into the subendothelial spaces, play a crucial role in all stages of atherosclerosis. Soluble forms of CAMs, probably derived from proteolytic shedding, are present in the circulation and their blood levels parallel the amount expressed on the cell surface. In patients with peripheral arterial disease (PAD), increased levels of soluble CAMs have been found during exercise-induced claudication, are associated with the presence, the severity and the extent of atherosclerosis in the arteries of the lower limbs, and portend a worse outcome. These findings have provided new insights into the pathophysiology of PAD and its consequences. However, further large population studies are needed to firmly establish whether increased levels of circulating CAMs give additive information to current risk assessment approaches, and to verify whether PAD patients with elevated levels of circulating CAMs would benefit from any specific therapy.

Angioplasty, Balloon↗
PubMed2006

Peripheral arterial disease and cardiovascular risk in Italy. Results of the Peripheral Arteriopathy and Cardiovascular Events (PACE) study.

OBJECTIVE: Our knowledge about the natural history of peripheral arterial disease (PAD) is derived from studies carried out almost exclusively in northern European and northern American populations. This study was aimed at defining mortality and cardiovascular morbidity of PAD patients in Italy. METHODS: From the lists of seven general practitioners, we identified all subjects aged 40-80 years (n = 4352). Of those reporting leg symptoms while walking at the Rose Questionnaire (n = 760), 60 (1.6% of the general population) had PAD, as evidenced by an ankle-brachial index of < 0.90 or reduced Doppler flow velocity. For each PAD patient, three sex and age-matched controls negative to the Rose Questionnaire were randomly selected from the general practice lists. RESULTS: After 24 months of follow-up, 15% of PAD patients died, 8% from cardiovascular disease, and 25% developed a non-fatal cardiovascular event. At Cox analysis, the presence of PAD was associated with an increased risk of all-cause mortality (relative risk 4.03; 95% confidence interval 1.50-10.84; P = 0.006), cardiovascular mortality (relative risk 7.77; 95% confidence interval 1.51-40.16; P = 0.014), and non-fatal cardiovascular events (relative risk 3.11; 95% confidence interval 1.41-6.80; P = 0.005). CONCLUSIONS: This Italian study shows that, in general practice, symptomatic PAD is associated with a four-fold increased risk of mortality and a nearly eight-fold increased risk of cardiovascular mortality. These figures are quite similar to those reported in northern European and northern American populations. General practitioners, who are the clinicians primarily and largely responsible for the care of these patients, should be alerted to the consequences of PAD.

Adult↗
PubMed2006

Prevention of distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction. A review of current status.

Distal embolization is a relatively common complication in primary angioplasty and is associated with poor perfusion and higher mortality. The aim of this article is to critically review literature on pharmacological and mechanical therapies to prevent distal embolization in patients undergoing primary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE, Pubmed) from January 1990 to March 2006 and scientific session abstracts (from January 1990 to March 2006) and oral presentation and/or expert slide presentations (from January 2002 to March 2006) (on TCT, AHA, ESC, ACC and EuroPCR websites). No language restrictions were enforced. Several pharmacological and mechanical therapies have been investigated to prevent distal embolization. Abciximab has been shown to reduce mortality, and its early administration may provide additional benefits in outcome due to improvement in preprocedural reperfusion. The results of randomized trials on adjunctive mechanical devices remain controversial. Even though they reduce distal embolization and improve myocardial perfusion, no benefits have been observed in terms of 30-day survival. Adjunctive abciximab has improved survival, and its early administration is to be recommended, particularly when transportation to a primary PCI center is needed. Pending the results of large randomized trials with long-term follow-up data, the routine use of adjunctive mechanical devices to prevent distal embolization cannot be recommended, though selective use of these devices might be considered when large thrombotic burden is present.

Abciximab↗
PubMed2005

Ischemic neoangiogenesis enhanced by beta2-adrenergic receptor overexpression: a novel role for the endothelial adrenergic system.

Beta2-adrenergic receptors (beta2ARs) are widely expressed, although their physiological relevance in many tissues is not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that beta2ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human beta2AR to the endothelium of the rat femoral artery and increased beta2AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that beta2AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in spontaneously hypertensive rats (SHR), whereas gene delivery of the G-protein-coupling defective mutant Ile164 beta2AR failed to provide ameliorations. Stimulation of endogenous and overexpressed beta2AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [3H]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The beta2AR also has novel effects on endothelial cell number through stimulation of proapoptosis and antiapoptosis pathways involving p38 mitogen-activated protein kinase and PI3-kinase/Akt activation. Therefore, beta2ARs play a critical role in endothelial cell proliferation and function including revascularization, suggesting a novel and physiologically relevant role in neoangiogenesis in response to ischemia.

Animals↗
PubMed2005

C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation.

OBJECTIVE: Inflammation plays a pivotal role in atherothrombosis. In addition to being a prognostic marker for major cardiovascular events, recent data indicate that C-reactive protein (CRP) might directly promote atherothrombosis by exerting direct effects on vascular cells. The aim of the present study was to determine whether CRP might affect the prothrombotic and proliferative characteristics of endothelial (ECs) and smooth muscle cells (SMCs). METHODS AND RESULTS: Incubation of ECs and SMCs with CRP resulted in a dose-dependent activation of cell proliferation, which was mediated by activation of the p44/42 MAP Kinase (ERK 1/2) pathway. In addition, CRP also induced tissue factor (TF) expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real time PCR. Activation of the transcription factor, NF-kappaB, by CRP was demonstrated by EMSA and by suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium. CONCLUSIONS: These data indicate that CRP exerts direct effects on ECs and SMCs by promoting proliferation and TF expression and support the notion that CRP, besides representing a marker of inflammation, is an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the vessel wall.

Animals↗
PubMed2005

Relation of brachial artery flow-mediated vasodilation to significant coronary artery disease in patients with peripheral arterial disease.

In patients at risk for coronary atherosclerosis, brachial artery flow-mediated dilation (FMD) rules out significant coronary artery disease (CAD). However, the value of this approach is unknown in patients with peripheral arterial disease who are at increased risk for CAD. This study assessed whether the noninvasive evaluation of endothelial function by brachial artery FMD rules out significant CAD by dipyridamole myocardial perfusion imaging (MPI) in patients with peripheral arterial disease who are asymptomatic for CAD. Forty-four patients with peripheral arterial disease who were asymptomatic for CAD underwent, in the same day, FMD evaluation and dipyridamole MPI using technetium-99m sestamibi single photon-emission computed tomography. MPI results were abnormal in 17 of 44 patients (39%). FMD was significantly less (6.0 +/- 2.3%) in patients with abnormal MPI results compared with those with normal MPI results (7.3 +/- 1.8%, p = 0.04). By multivariate analysis, FMD was the only significant predictor of abnormal MPI results (odds ratio 0.63, p = 0.02). Receiver-operating characteristic curve analysis assessing the ability of FMD to identify patients with summed stress scores > or =3 yielded an area under the curve of 0.74 (p = 0.009). A FMD value >6% provided 92% negative predictive power to rule out abnormal MPI results, with sensitivity of 79% and specificity of 73%. In conclusion, the noninvasive evaluation of endothelial function by FMD has high negative predictive accuracy and good sensitivity and specificity to detect abnormal MPI results in patients with peripheral arterial disease. Thus, it may represent a valuable screening test to rule out significant CAD in these patients.

Arterial Occlusive Diseases↗
PubMed2005

Role of beta2 adrenergic receptors in human atherosclerotic coronary arteries.

BACKGROUND: Adrenergic regulation of coronary vasomotion is balanced between alpha1-adrenergic-mediated (alpha1-AR) constriction and beta2-adrenergic-mediated (beta2-AR) relaxation. This study aimed at assessing the role of beta2-ARs in normal, mildly atherosclerotic, and stenotic human coronary arteries. METHODS AND RESULTS: During intracoronary (IC) infusion of increasing doses of the beta2-AR agonist salbutamol (0.15, 0.3, and 0.6 mug/min) and the endothelial vasodilator acetylcholine (1, 3, and 10 microg/min), we measured (1) changes in lumen diameter (LD) by quantitative coronary angiography in 34 normal, 55 mildly atherosclerotic, and 42 stenotic coronary artery segments and (2) changes in average peak velocity (APV) and coronary blood flow (CBF) with the use of Doppler flow wire in 11 normal, 10 mildly atherosclerotic, and 11 stenotic coronary arteries. In 6 of 11 stenotic coronary arteries, the protocol was repeated after an IC bolus (12 microg/kg) of the alpha-adrenergic blocker phentolamine. In 6 of 11 normal coronary arteries, the protocol was repeated after an IC infusion (60 micromol/min) of N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide inhibitor. Neither salbutamol IC infusion nor acetylcholine significantly changed heart rate or blood pressure, whereas L-NMMA slightly increased blood pressure. In normal coronary arteries, salbutamol increased LD (LD max %: 11+/-2, P<0.05), APV (APV max %: 53+/-17, P<0.05), and CBF (CBF max %: 57+/-17, P<0.05), whereas L-NMMA caused a blunted APV (APV max %: 27+/-6, P<0.05) and CBF (CBF max %: 29+/-6, P<0.05) response to salbutamol. In mildly atherosclerotic coronary arteries, the salbutamol increase in LD (LD max %: 10+/-2, P<0.05), APV (APV max %: 33+/-12, P<0.05), and CBF (CBF max %: 37+/-12, P<0.05) was preserved. In stenotic coronary arteries, salbutamol induced a paradoxical reduction in LD (LD max %: -6+/-2, P<0.05), APV (APV max %: -15+/-9, P<0.05), and CBF (CBF max %: -15+/-6, P<0.05), which was no longer observed after phentolamine. Acetylcholine increased LD (LD max %: 14+/-3, P<0.05), APV (APV max %: 61+/-20, P<0.05), and CBF (CBF max %: 67+/-19, P<0.05) in normal coronary arteries. In mildly atherosclerotic coronary arteries, acetylcholine induced a significant reduction in LD (LD max %: -15+/-2, P<0.05) and no changes in APV (APV max %: -6+/-13, P=NS) and CBF (CBF max %: -10+/-13, P=NS). In stenotic coronary arteries, acetylcholine significantly reduced LD (LD max %: -15+/-3, P<0.05), APV (APV max %: -15+/-9, P<0.05), and CBF (CBF max %: -15+/-6, P<0.05). CONCLUSIONS: In severely atherosclerotic coronary arteries, beta2-adrenergic vasodilatation is impaired, and this might contribute to alter the vasomotor balance, further precipitating myocardial ischemia during sympathetic activation.

Acetylcholine↗
PubMed2005

The identification of reversible dysfunctional myocardium is influenced by the severity of contractile dysfunction and by the length of follow-up.

OBJECTIVES: To evaluate the influence of the severity of regional myocardial dysfunction and of the length of follow-up on the identification of myocardial viability with rest-redistribution Tl single photon emission computed tomography (SPECT) and low-dose dobutamine echocardiography (LDDE). METHODS: Twenty-six patients with chronic coronary artery disease and wall motion abnormalities, candidates for revascularization, were included in this study. All patients underwent, in the same week, Tl SPECT and LDDE for pre-revascularization evaluation of myocardial viability. Reversibility of regional dysfunction was assessed by two-dimensional echocardiography, 40+/-20 days (early follow-up) and 12+/-5 months (late follow-up) after revascularization. RESULTS: In a/dyskinetic segments, Tl SPECT showed similar values of sensitivity (78% vs. 71%, P=NS) and slightly higher values of specificity (43% vs. 18%, P<0.01) compared to hypokinetic segments, in predicting functional recovery at early follow-up. No significant changes were observed in the diagnostic accuracy of Tl SPECT at late follow-up. On the contrary, LDDE provided significantly lower values of sensitivity (56% vs. 94%, P<0.05) and higher values of specificity (73% vs. 9%, P<0.01) in a/dyskinetic compared to hypokinetic segments. Specificity of LDDE in a/dyskinetic segments significantly increased from early (73%) to late follow-up (95%; P<0.05). Similarly, positive predictive value in a/dyskinetic segments significantly increased from early (69%) to late follow-up (96%; P<0.05). CONCLUSIONS: The severity of regional dysfunction and the length of follow-up significantly influence the diagnostic accuracy of LDDE but not of rest-redistribution Tl SPECT in the identification of myocardial viability.

Adult↗
PubMed2005

Adhesion molecules and cardiovascular risk in peripheral arterial disease. Soluble vascular cell adhesion molecule-1 improves risk stratification.

Although intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) play a relevant role in atherosclerosis, little is known about the prognostic impact of their soluble forms (s) in patients with peripheral arterial disease (PAD). The aim of this prospective study was to verify whether plasma levels of sICAM-1 and sVCAM-1 predict cardiovascular risk in PAD, and improve the prognostic value of the ankle/brachial index (ABI) alone. Accordingly, plasma levels of sICAM-1 and sVCAM-1, and the ABI were measured in 75 PAD patients who were monitored for a mean of 24+/-13 months. Twenty-two (29.3%) patients had a cardiovascular event (15 coronary, 3 cerebrovascular and 4 peripheral events). Plasma levels of sVCAM-1 were 618+/-258 ng/mL in patients with and 496+/-164 ng/mL in those without an event (p=0.016). The corresponding sICAM-1 values were 344+/-239 ng/mL and 275+/-99 ng/mL (p=0.079). The cardiovascular event rate was higher in patients with sVCAM-1 levels above the median than in those with sVCAM-1 below the median (p=0.0027 by log rank test). Independent predictors of events were sVCAM-1 levels above the median (p=0.005) and an ABI below the median (p=0.001). Amongst patients with ABI below the median, the occurrence of sVCAM-1 above the median was associated with a 3.4-fold increase in risk (95% CI 1.308 to 9.573, p=0.013). In conclusion, increased plasma levels of sVCAM-1 have a negative prognostic impact in PAD and improve the predictive value of ABI, which is currently the most powerful risk indicator in these patients.

Aged↗