Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial.

BACKGROUND: Ticagrelor is a reversibly binding, direct-acting, oral, P2Y12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction. METHODS: To determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart. DISCUSSION: Ticagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes. TRIAL REGISTRATION: EudraCT No. 2016-004746-28. No. NCT02701140.  TRIAL STATUS: Information provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019. TRIAL SPONSOR: Fondazione Policlinico Universitario A. Gemelli - Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.

Anti-HPV Nanoemulsified-Imiquimod: A New and Potent Formulation to Treat Cervical Cancer.

Cervical cancer is associated with the human papilloma virus (HPV) and nowadays is the fourth most frequent cancer among women. One of the treatments for this disease is based on the application of imiquimod. In this study, we postulated that the use of imiquimod in nanoemulsion results in a better antitumoral effect than the drug administered in its nonencapsulated form for the treatment of cervical cancer. Permeability studies using vaginal mucosa, as membrane, and in vitro studies involving cervical cancer cells (viability, clonogenic assay, and cell death analysis) were performed. We showed that low amount of encapsulated imiquimod permeated the vaginal mucosa. However, a higher percentage of cells died after the treatment with low amount (3.0 µmol L-1) of the formulation compared to the free drug. In addition, the innovative formulation presented a combinatory mechanism of cell death involving autophagy and apoptosis. Our results demonstrate that the imiquimod-loaded nanoemulsioncan be an alternative product for the treatment of cervical cancer validating the hypothesis.

Imiquimod-loaded nanocapsules improve cytotoxicity in cervical cancer cell line.

This paper proposes the development of imiquimod-loaded polymeric nanocapsules formulation for the treatment of cervical cancer. The mechanism of death involved in the reduction of the cell viability as well as the production of an inflammation marker (IL-6) after the treatment in cell line SiHa have been evaluated. The formulation has significantly decreased the viability of the cells in a time-dependent manner, after 24, 48 and 72 h. Additionally, results showed a cellular decrease of almost 80% of the cells after 72 h of treatment. The formulation induced death by apoptosis, necrosis, autophagy, and increased the percentage of SubG1subpopulation of SiHa cells after 72 h. After the same time-interval, the formulation significantly prevented the appearance of colonies, showing effectiveness against SiHa. Finally, the formulation stimulated SiHa cells to release IL-6. These findings open new possibilities for the development of aqueous nanosuspension containing imiquimod as a novel strategy for the treatment of cervical cancer.

Doxazosin nanoencapsulation improves its in vitro antiproliferative and anticlonogenic effects on breast cancer cells.

Doxazosin has been evaluated for the treatment of several types of cancer. Here, the antitumor effect of the nanoencapsulated form of doxazosin was evaluated in an in vitro model of breast cancer (MCF7 cell line). Doxazosin-loaded polymeric nanocapsules (DXZ-NC) were produced by interfacial deposition of preformed polymer with homogeneous aspect, spherical shape, mean diameter of about 130nm, positive zeta potential (+5mV), and encapsulation efficiency close to 35%. The Alamar Blue® assay and cell counting were carried out to assess cell viability and cell number, respectively. Mechanism of death was evaluated by Annexin/Propidium Iodide staining, while the long-term response was assessed using the clonogenic assay. Nuclear morphometric analysis was investigated using the NMA technique. A significant decrease in cell viability and clonogenicity was observed after the treatment with DXZ-NC when compared to the non-encapsulated drug. All treatments induced apoptosis as the main mechanism of toxicity. In conclusion, the nanoencapsulation of doxazosin improved its in vitro effects in MCF7 cells, without changing the mechanism of cell death underlying its toxicity. This approach was fundamental to reduce the long-term in vitro ability of the remaining tumor cells to form new colonies after the treatment, potentially reducing the risk of tumor recurrence.

A critical overview on ticagrelor in acute coronary syndromes.

Until a few years ago, the mainstay of anti-platelet therapy in patients with acute coronary syndrome (ACS) was the combination of aspirin and clopidogrel, a P2Y12 receptor inhibitor. However, current clinical practice has now changed with the introduction of ticagrelor, a more potent cardiovascular drug than clopidogrel, without the limitations related to clopidogrel therapy. In this review, we provide a critical overview of ticagrelor in ACS, highlight the results with ticagrelor in several subgroups of patients and discuss the future trials.

Low-molecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis.

BACKGROUND: The aim of the current study was to perform two separate meta-analyses of available studies comparing low-molecular-weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST-elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. METHODS: All-cause mortality was the pre-specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. RESULTS: Ten studies comprising 16,286 patients were included. The median follow-up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41-0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49-0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta-regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). CONCLUSIONS: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta-analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.

Early vs. delayed invasive strategy in patients with acute coronary syndromes without ST-segment elevation: a meta-analysis of randomized studies.

Although early percutaneous coronary intervention has been demonstrated to reduce the risk of mortality in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), there are emerging conflicting data as to whether the catheterization needs to be done very early or whether it could be delayed while the patient receives medical therapy. The aim of the current study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing early vs. delayed invasive strategies for NSTE-ACS patients. Medline/CENTRAL and the Web were searched for RCTs comparing early vs. delayed invasive strategies for NSTE-ACS patients. The primary endpoint was all cause mortality, whereas myocardial infarction (MI), coronary revascularizations and 30-day major bleeding complications were secondary end points. Fixed or random effects models were used based on statistical heterogeneity. As a sensitivity analysis, Bayesian random effects meta-analysis was performed in addition to the classical random effects meta-analysis. A total of 5 RCTs were finally included, enrolling 4155 patients. As compared with a delayed strategy, an early invasive approach did not significantly reduce the rates of death [odds ratio (OR) 95% confidence interval (95% CI) = 0.81 (95% CI 0.60-1.09), P = 0.17], MI [OR = 1.18 (95% CI 0.68-2.05), P = 0.55] or revascularizations [OR = 0.97 (0.77-1.24), P = 0.82]. There was a not significant trend toward fewer major bleeding complications for the early invasive approach [OR (95% CI) = 0.76 (0.55-1.04), P = 0.08]. The present meta-analysis shows that for NSTE-ACS patients a routine early invasive strategy does not significantly improve survival nor reduce MI and revascularization rates as compared with a delayed approach.

NTPDase and 5' ecto-nucleotidase expression profiles and the pattern of extracellular ATP metabolism in the Walker 256 tumor.

In this study, we evaluated the NTPDases and ecto-5'-nucleotidase (CD73) expression profiles and the pattern of adenine nucleotide hydrolysis in rats submitted to the Walker 256 tumor model, 6, 10 and 15 days after the subcutaneous inoculation. Using RT-PCR analysis, we identified mRNA for all of the members of the ecto-nucleoside triphosphate diphosphohydrolase family investigated and a 5'-nucleotidase. By quantitative real-time PCR, Entpd1 (Cd39) and Entpd2 (Cd39L1) and CD73 were identified as the dominant genes expressed by the Walker 256 tumor, at all times studied. Extracellular adenine nucleotide hydrolysis by the Walker 256 tumor was estimated by HPLC analysis. Rapid hydrolysis of extracellular ATP by the tumor cells was observed, leading to the formation of adenosine and inosine in cells obtained from solid tumors at 6 and 10 days after inoculation. Cells obtained from solid tumors at 15 days of growth presented high levels of AMP and presented adenosine as a final product after 90 min of incubation. Results demonstrate that the presence of NTPDases and 5'-nucleotidase enzymes in Walker 256 tumor cells may be important for regulation of the extracellular adenine nucleotides/adenine nucleoside ratio, therefore leading to tumor growth.

[Isolated congenital coronary fistula in adult population: discussion a clinical case and review of current literature]. / Fistola coronarica congenita isolata in età adulta: descrizione di un caso e revisione della letteratura.

We describe a case of a 56 year-old man with a history of chest pain. No evidence of myocardial ischemia or arrhytmias was observed. Echocardiographic examination in Emergency Department evidenced aortic root dilatation. Angio CT excluded aortic dissection. Trans esophageous Echocardiography (TEE) correctly identified an arterial fistula between the right coronary artery and superior vena cava, confirmed by angio CT 3-D reconstruction and coronarography. The definitive diagnosis was made after integrated approach (using TTE, TEE, CT, coronarography). The anatomic features of the fistula and the aortic root were examinated. Actually the patient is being followed with serial clinical and echocardiography examination for monitoring hemodynamic overload by fistula and size of aortic root for potential surgical correction. Current literature for incidence, diagnosis and the treatment of coronary fistulas is discussed.

[Prevalence of aneurysm of the interatrial septum in the general population and in patients with a recent episode of cryptogenetic ischemic stroke: a tissue harmonic imaging transthoracic echocardiography study in 5.631 patients]. / Prevalenza di aneurisma del setto interatriale nella popolazione generale e in pazienti con recente stroke criptogenetico: studio ecocardiografico transtoracico con seconda armonica tessutale in 5.631 pazienti.

Cerebral ischemia is among the principal causes of mortality and morbidity in industrialized countries being responsible of 10-12% of all deaths and of an elevated number of permanent disability. The cardio-embolic forms may be responsible of the 30-35% of cerebrovascular acute syndrome, nevertheless in a significant percentage of cases, especially among young people, cerebral ischemic episodes are not induced by these cardio-embolic forms: these cases are defined as cryptogenetic stroke/TIA. In these patients cardiac abnormalities represented by an aneurysm of the interatrial septum (ASA) and by a patent foramen ovale (PFO) have been frequently observed. The purpose of our prospective, study was to evaluate, through transthoracic echocardiography and tissue harmonic imaging (ETT-THI), the prevalence of ASA in the general population (group A) and the prevalence of ASA-FOP in a subgroup of patients with recent episode of cryptogenetic ischemic stroke/TIA (group B). We studied in a prospective manner from January 1 2003 to October 31t 2004 n. 5.631 patients. The presence of ASA was found in 3.2% of patients of group A, while in patients of group B we identified an ASA in 32% and a POF in 42% of the cases. Using a ETT-THI, our study shows in a wide range of a non selected population a prevalence of ASA greater than in previous studies. Such high prevalence in the general population of patients submitted to echocardiography and the higher frequency in subjects with recent cryptogenetic stroke, suggests to search carefully these abnormalities at the level of the interatrial septum using the harmonic imaging method.

Coronary artero-venous gradient of endogenous urokinase.

Experimental data indicate that urokinase-type plasminogen activator (u-PA) contributes significantly to endogenous fibrinolysis and vascular remodeling in proportion to its local concentrations. In humans, however, it is not known whether u-PA levels vary at different sites and across specific vascular beds. We investigated possible regional and artero-venous differences in plasma u-PA concentrations in 15 patients undergoing cardiac catheterization. Three pairs of simultaneous samples were taken from: (1) the ascending aorta and coronary sinus; (2) left ventricle and right atrium; (3) femoral artery and femoral vein. Single-chain urokinase-type plasminogen activator (scu-PA) was measured by bioimmunoassay, and total u-PA antigen (including scu-Pa and two-chain urokinase-type plasminogen activator complexed with inhibitors (tcu-PA)) by enzyme-linked immunosorbent assay. Scu-PA represented, on average, 51+/-15% of total u-PA concentrations. Scu-PA and total u-PA levels were correlated (r=.72, P<.0001) and did not differ significantly among the arterial or venous locations. There was a small but consistent increase in mean (+/-standard deviation (S.D.)) scu-PA concentrations from all arterial to all venous samples (1.5+/-0.6 vs. 1.6+/-0.5 ng/ml, P=.038) and from ascending aorta to coronary sinus (1.6+/-0.5 vs. 1.7+/-0.6 ng/ml, P=.046). Similarly, total u-PA levels increased from femoral artery to femoral vein (2.9+/-0.7 vs. 3.0+/-0.8 ng/ml, P<.001). In contrast, across the lungs, no significant concentration-gradient was seen in either scu-PA or total u-PA. The changes in total u-PA roughly followed those of scu-PA. These data identify an artero-venous gradient in human plasma u-PA across the coronary and peripheral beds, but not across the lungs, suggesting differences in u-PA kinetics according to vascular location.

Enhanced response of blood monocytes to in vitro lipopolysaccharide-challenge in patients with recurrent unstable angina.

BACKGROUND: C-reactive protein (CRP) plasma levels have been associated with short- and long-term occurrence of coronary events. We investigated whether circulating inflammatory cell responsiveness to low-grade stimuli could contribute to the reported association between CRP and coronary events. METHODS AND RESULTS: We studied 32 patients with unstable angina who were followed for 24 months and were free of symptoms for 6 months (group 1): 19 patients had persistently high CRP levels (>0.3 mg/dL) (group 1A); 13 patients had normal CRP levels (group 1B). During the follow-up, 12 (63%) group 1A but no group 1B patients developed an infarction or recurrence of unstable angina (P<0.001). Eighteen patients with chronic stable angina (group 2) and 18 healthy subjects (group 3) were studied as controls. Interleukin (IL)-6 production (median, range) by peripheral blood mononuclear cells after 4 hours of in vitro stimulation with 1 ng/mL lipopolysaccharide (LPS) was significantly higher in group 1A (4526 pg/mL, 3042 to 10 583 pg/mL) than in group 1B (1752 pg/mL, 75 to 3981 pg/mL), group 2 (707 pg/mL, 41 to 3275 pg/mL), and group 3 (488 pg/mL, 92 to 3503 pg/mL) (all P<0.001). No significant differences were observed among the other groups. IL-6 production after LPS-challenge was correlated with baseline CRP levels (r=0.42, P=0.005). CONCLUSIONS: Mononuclear cells of patients with recurrent phases of instability exhibit an enhanced production of IL-6 in response to low-dose of LPS, correlated with baseline CRP levels, 6 months after the last acute event. This persisting enhanced acute-phase responsiveness may help explain the association between CRP and acute coronary events.

Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X.

The presence of myocardial ischemia in syndrome X (chest pain, "ischemia-like" electrocardiogram changes, and normal coronary angiograms) is uncertain possibly because, when focally distributed, it may not cause contractile dysfunction or lactate production. We measured lipid hydroperoxides (ROOHs) and conjugated dienes (CDs), two sensitive, independent markers of ischemia-reperfusion oxidative stress, in paired aortic and great cardiac vein blood samples before and after pacing-induced tachycardia in nine patients with syndrome X. Diagnostic ischemic S-T segment changes during pacing were followed by a consistent increase in ROOH and CD levels in the great cardiac vein (from 4.83 +/- 1.18 micromol/l at baseline to 7.88 +/- 1.12 micromol/l and from 0.038 +/- 0.002 to 0.051 +/- 0.003 arbitrary units, respectively, P < 0.01). In controls, ROOH and CD levels did not change after pacing. The large postpacing cardiac release of lipid peroxidation products, consistently observed in all patients and similar to that previously observed after ischemia caused by percutaneous transluminal coronary angioplasty, is consistent with an ischemic origin of syndrome X.

Oxidative stress in ischemia-reperfusion injury: assessment by three independent biochemical markers.

BACKGROUND: Oxidative stress plays a key role in ischemia-reperfusion injury, causing peroxidation of tissue lipids and proteins. However, it is debated whether brief ischemic episodes are sufficient to cause detectable oxidative stress in humans, since biochemical markers used so far in the setting of percutaneous transluminal coronary angioplasty (PTCA) gave conflicting results. METHODS: We determined lipid hydroperoxides (ROOHs), conjugated dienes (CD) and total radical-trapping antioxidant capacity (TRAP), three different independent markers of oxidative stress, in aortic and great cardiac vein blood of 5 patients undergoing PTCA before a single balloon inflation lasting 115 +/- 38 s (t0), and 1 min (t1), 5 min (t5), 15 min (t15) after balloon deflation (Group 1). ROOHs and CD were also determined in aortic and great cardiac vein blood of 5 patients with mitral valve disease (Group 2). RESULTS: In Group 1, great cardiac vein levels of ROOHs and CD at t1 increased by 219% and 79%, respectively, compared to t0 (p < 0.01); this sharp and consistent increase persisted up to t15 (+189% and +63%, respectively, compared to t0; p < 0.01). Great cardiac vein levels of TRAP were significantly lower than aortic levels at t0, and exhibited a further decrease at tl. No significant differences in aortic and great cardiac vein levels of ROOHs and CD at t0 were observed between Group 1 and Group 2. CONCLUSIONS: The three methods we used showed a remarkable sensitivity for the detection of post-ischemic reperfusion injury in cardiac venous blood and may be useful for detecting small foci of ischemia-reperfusion injury in microvascular angina.

Large, sustained cardiac lipid peroxidation and reduced antioxidant capacity in the coronary circulation after brief episodes of myocardial ischemia.

OBJECTIVES: We sought to investigate whether a brief episode of myocardial ischemia produces a detectable cardiac oxidative stress in patients undergoing elective coronary angioplasty (PTCA). BACKGROUND: Although cardiac oxidative stress has been clearly demonstrated in experimental models of ischemia-reperfusion, its presence in patients after transient myocardial ischemia is still unclear. METHODS: In order to evaluate oxidative stress in ischemic cardiac regions, plasma conjugated dienes (CD), lipid hydroperoxides (ROOHs) and total antioxidant capacity (TRAP), independent indexes of oxidative stress, were measured in the aorta and great cardiac vein (GCV) before (t0), 1, (t1), 5 (t5) and 15 min (t15) after first balloon inflation in 15 patients undergoing PTCA on left anterior descending coronary artery (Group 1); six patients with right coronary artery stenosis (Group 2), which is not drained by the GCV, were studied as controls. RESULTS: In Group 1 at baseline, CD and ROOHs levels were higher in GCV than in aorta (p < 0.01 for both), and TRAP levels were lower (p < 0.01). Aortic levels of CD, ROOHs and TRAP did not change at any time after to; venous levels of CD and ROOHs levels markedly increased at t1, at t5 and remained elevated at t15 (p < 0.01 for all comparisons vs. to); venous levels of TRAP decreased at t1 and t5 (p < 0.01 vs. t0) and returned to normal at t15. In Group 2, CD, ROOHs and TRAP levels were similar in the aorta and GCV and did not change throughout the study. CONCLUSIONS: Short episodes of myocardial ischemia during PTCA induce a sustained oxidative stress, which is detectable in the venous effluent of reperfused myocardium.

Effect of protein-modifying reagents on ecto-apyrase from rat brain.

We have tested several chemical modifiers to investigate which amino acid residues, present in the primary structure of the ecto-apyrase, could be involved in catalysis. Synaptosomes from cerebral cortex of rats were prepared and the ATP diphosphohydrolase activity was assayed in absence or the presence of the modifiers. Percentages of residual activity for ATPase and ADPase obtained when the following reagents were tested, are respectively: phenylglyoxal (an arginine group modifier) 17 and 30%; Woodward's reagent (a carboxylic group modifier) 33 and 23%; Koshland's reagent (a tryptophan group modifier) 10 and 12%; maleic anhidride (an amino group modifier) 11 and 25% and carbodiimide reagent (a carboxylic group modifier) 56 and 72%. Otherwise, PMSF, a seryl protein modifier and DTNB, a SH-group modifier did not affect either ATPase or ADPase activity. Inhibitions observed after treatment with phenylglyoxal and Woodward's reagent were significantly prevented when the synaptosomal fraction was preincubated with ATP and ADP, indicating that the arginine and the side chain of glutamate or aspartate (carboxyl groups) participate in the structure of the active site. This interpretation was confirmed by using GTP and GDP, two other apyrase substrates. Phenylglyoxal and Woodward's reagent also inhibited the GTPase and GDPase activities and this inhibition was prevented by preincubation with these substrates.

The variable role of inflammation in acute coronary syndromes and in restenosis.

Inflammation has recently been shown to be an important pathogenetic component of atherosclerosis in general and of acute coronary syndromes in particular. Not only activated inflammatory cells have been found in the plaques, but, more interestingly, also activated circulating inflammatory cells as well as elevated levels of systemic markers of inflammation have been described. Among these, C-reactive protein is of clinical value, as its levels are associated with the outcome. Inflammation is important also in triggering the mechanisms of restenosis and CRP has been recently described as a useful pre-procedure marker of risk of restenosis. The cause of inflammation, what triggers the shift from an indolent disease to the acute coronary syndromes and the more appropriate therapies are still a matter of debate.

Effects of atrial pacing on arterial and coronary sinus endothelin-1 levels in syndrome X.

Syndrome X may be caused by a coronary microvascular dysfunction, possibly due to abnormalities in coronary endothelial function. Previous studies suggested that endothelin-1 (ET-1) might be involved in the pathogenesis of syndrome X. Baseline arterial and coronary sinus ET-1 levels were measured in 13 patients with syndrome X (10 women, 52+/-7 years) and in 8 control patients (5 women, 46+/-11 years). ET-1 was also measured after atrial pacing in 12 patients with syndrome X and all controls. To simultaneously assess the activity of nitric oxide, guanosine 3'-5'-cyclic monophosphate (cGMP) was also measured in 11 patients with syndrome X and 7 controls. Baseline arterial (2.27+/-0.46 vs. 1.90+/-0.22 pg/ml, p<0.05) and coronary sinus (2.03+/-0.43 vs. 1.68+/-0.28 pg/ml, p = 0.06) ET-1 plasma levels were higher in patients than in controls. After pacing, arterial ET-1 levels did not change in either group and coronary sinus ET-1 levels were also unchanged in controls. In contrast, coronary sinus ET-increased significantly in response to atrial pacing in patients with syndrome X (p = 0.023), and differences between coronary sinus ET-1 levels of patients with syndrome X and controls after pacing became highly significant (2.22+/-0.45 vs. 1.69+/-0.20 pg/ml, respectively, p = 0.006). No significant differences in arterial and coronary sinus cGMP concentrations were found between the 2 groups, both at baseline and after pacing. Our findings suggest that an increased vasoconstrictor activity of microvascular endothelium is present in at least some patients with syndrome X and may be involved in the pathogenesis of the syndrome.

Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty.

OBJECTIVES: We sought to investigate whether early and late outcome after percutaneous transluminal coronary angioplasty (PTCA) could be predicted by baseline levels of acute-phase reactants. BACKGROUND: Although some risk factors for acute complications and restenosis have been identified, an accurate preprocedural risk stratification of patients undergoing PTCA is still lacking. METHODS: Levels of C-reactive protein (CRP), serum amyloid A protein (SAA) and fibrinogen were measured in 52 stable angina and 69 unstable angina patients undergoing single vessel PTCA. RESULTS: Tertiles of CRP levels (relative risk [RR] = 12.2, p < 0.001), systemic hypertension (RR = 4.3, p = 0.046) and female gender (RR = 4.1, p = 0.033) were the only independent predictors of early adverse events. Intraprocedural and in-hospital complications were observed in 22% of 69 patients with high serum levels (>0.3 mg/dl) of CRP and in none of 52 patients with normal CRP levels (p < 0.001). Tertiles of CRP levels (RR = 6.2, p = 0.001), SAA levels (RR = 6.0, p = 0.011), residual stenosis (RR = 3.2, p = 0.007) and acute gain (RR = 0.3, p = 0.01) were the only independent predictors of clinical restenosis. At one-year follow-up, clinical restenosis developed in 63% of patients with high CRP levels and in 27% of those with normal CRP levels (p < 0.001). CONCLUSIONS: Preprocedural CRP level, an easily measurable marker of acute phase response, is a powerful predictor of both early and late outcome in patients undergoing single vessel PTCA, suggesting that early complications and clinical restenosis are markedly influenced by the preprocedural degree of inflammatory cell activation.

Enhanced inflammatory response in patients with preinfarction unstable angina.

OBJECTIVES: We assessed the extent and the time course of the acute phase response following myocardial cell necrosis and its relationship with the presence of preinfarction unstable angina (UA). BACKGROUND: Elevated levels of acute phase proteins have been reported in patients with UA and in patients with acute myocardial infarction (MI). METHODS: C-Reactive Protein (CRP), serum amyloid A protein (SAA) and interleukin-6 (IL-6) were measured in 36 patients with MI admitted within 3 h from symptoms onset. All patients had normal levels of creatine kinase and of troponin T on admission, rising above diagnostic levels within 6 to 12 h. Blood samples for CRP, SAA and IL-6 measurements were taken on admission, at 6, 24, 48, 72 h and at discharge. RESULTS: Twenty of the 36 patients studied presented an unheralded MI (Group 1); the remaining 16 patients had symptoms of unstable angina in the preceding 7 days (Group 2). Group 2 patients have much higher levels of CRP and SAA on admission (median values 8.8 vs. 3 mg/L and 28 vs. 3.4 mg/L, respectively, all p<0.001). Following the necrotic insult, despite similar infarct size and clinical signs of reperfusion, Group 2 patients had strikingly higher peaks of IL-6 (median values 85.2 vs. 19 pg/ml, p<0.05), CRP (50 vs. 31.4 mg/L, p<0.05) and SAA (228 vs. 45 mg/L, p<0.001). CONCLUSIONS: Our data demonstrated that the acute phase response is greatly enhanced in patients with preinfarction UA compared with those presenting with an unheralded MI. The significant differences in acute phase response observed in these two clinical presentations of MI indicate a major difference in their underlying pathogenetic components.