Synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid.

A synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid has been developed, thereby significantly shortening the known literature procedures for the syntheses of these unnatural amino acids. With a simple adjustment of the reaction conditions, we were able to obtain either pure cis or trans acid. Optical resolution was accomplished via diastereomeric salt formation or alternatively via chromatography on a chiral stationary phase. Finally, ab initio calculations gave an explanation for the observed cis selectivity in the initial step.

Periprocedural management and in-hospital outcome of patients with indication for oral anticoagulation undergoing coronary artery stenting.

PURPOSE: In patients on oral anticoagulation (OAC) undergoing coronary stenting (PCI-S), procedural management and in-hospital outcome have never been specifically and prospectively investigated. Also, the contribution of early bleeding to the relevant hemorrhagic rate reported at follow-up with triple therapy of OAC, aspirin, and clopidogrel is largely unknown. METHODS: Consecutive patients with indication for OAC undergoing PCI-S at 5 centers were enrolled and prospectively evaluated. RESULTS: Out of 3410 patients undergoing PCI-S in the study period, indication for OAC was present in 4.8%. Femoral approach and bare metal stents were the most frequently used. During PCI-S, OAC was continued in about 30% of patients, whereas in about 20% heparin bridging was carried out. Glycoprotein IIb/IIIa inhibitors were rarely used (11%), whereas a standard bolus of unfractionated heparin was given in 93% of cases. Major adverse cardiovascular events (MACE) occurred in 4.8% of patients and major bleeding in 4.3%. No predictors of MACE or bleeding were identified, although the femoral approach was of borderline significance for major bleeding (OR 4.6, 95% CI 1.0-20.8; P = 0.05). A history of previous hemorrhage (OR 5.3, 95% CI 1.6-18.1; P = 0.007) predicted Carbofilm-coated stent implantation. CONCLUSIONS: A limited, albeit clinically relevant, proportion of patients undergoing PCI-S has indication for OAC. Procedural management appears not substantially different from that of common patients. In-hospital major bleeding is relevant and should be taken into account when evaluating the overall hemorrhagic rate at a medium- to long-term follow-up.

Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration.

Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.

Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres.

Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves aqueous solubility by at least 50-fold, and markedly decreases nonspecific binding (NSB) as measured by CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits regarding NSB or solubility, whereas substitutions with cubane-1,4-diyl showed improvements for both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl-substituted molecules.

Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial.

BACKGROUND: Whether cyclosporine A (CsA) has beneficial effects in reperfused myocardial infarction (MI) is debated. OBJECTIVES: This study investigated whether CsA improved ST-segment resolution in a randomized, multicenter phase II study. METHODS: The authors randomly assigned 410 patients from 31 cardiac care units, age 63 ± 12 years, with large ST-segment elevation MI within 6 h of symptom onset, Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primary percutaneous coronary intervention, to 2.5 mg/kg intravenous CsA (n = 207) or control (n = 203) groups. The primary endpoint was incidence of ≥70% ST-segment resolution 60 min after TIMI flow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4, left ventricular (LV) remodeling, and clinical events at 6-month follow-up. RESULTS: Time from symptom onset to first antegrade flow was 180 ± 67 min; a median of 5 electrocardiography leads showed ST-segment deviation (quartile [Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior. ST-segment resolution ≥70% was found in 52.0% of CsA patients and 49.0% of controls (p = 0.55). Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087 to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l in controls (p = 0.85). The 2 groups did not differ in LV ejection fraction on day 4 and at 6 months. Infarct site did not influence CsA efficacy. There were no acute allergic reactions or nonsignificant excesses of 6-month mortality (5.7% CsA vs. 3.2% controls, p = 0.17) or cardiogenic shock (2.4% CsA vs. 1.5% controls, p = 0.33). CONCLUSIONS: In the CYCLE (CYCLosporinE A in Reperfused Acute Myocardial Infarction) trial, a single intravenous CsA bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6 months. (CYCLosporinE A in Reperfused Acute Myocardial Infarction [CYCLE]; NCT01650662; EudraCT number 2011-002876-18).

[Hospital epidemiology of ST-segment elevation myocardial infarction and feasibility of primary percutaneous coronary intervention in an interhospital network: data from a multicenter, prospective and observational study VENERE (VENEto acute myocardial infarction REgistry]. / Epidemiologia ospedaliera dell'infarto miocardico acuto con sopraslivellamento del tratto ST ed applicabilità dell'angioplastica primaria nel contesto di rete interospedaliera: studio prospettico osservazionale e multicentrico VENERE (VENEto acute myocardial infarction REgistry).

BACKGROUND: Primary percutaneous coronary intervention (pPCI) is the most effective reperfusion treatment of acute ST-segment elevation myocardial infarction (STEMI), but logistic- and organization-related problems affect its feasibility. The aim of this study was to investigate a) the requirements of reperfusion therapies, and b) the feasibility of pPCI as suggested by the current guidelines, in the Veneto Region. METHODS: With the aim to treat with pPCI most of the patients with high-risk STEMI regardless of the type of admitting hospital, a single treatment protocol was developed and shared by the majority of Cardiology Departments in the Veneto Region. Data of all consecutive patients with STEMI were prospectively recorded and subsequently and independently compared with administrative data. RESULTS: In 28 participating hospitals, 1160 consecutive patients with STEMI were enrolled during a 6-month period: in 999 symptom onset was < 12 hours. Based on the registry data, it is possible to estimate that 697 patients/million of inhabitants/year are admitted in Cardiology Departments with the initial diagnosis of STEMI: 86% are admitted < 12 hours from symptom onset and 58% of them have at least one characteristic of high risk. The strategy of immediate coronary angiography and possible PCI was carried out in 52.3% of eligible patients: in 55.8 and 47.5% of high- and low-risk STEMI and from 17.1 to 75.1% based on the type of admitting hospital. Recanalization with pPCI was obtained < 90 min from the diagnosis in 70 and 32% of patients treated on site and transferred, respectively. CONCLUSIONS: The absolute number of patients with STEMI eligible for reperfusion therapies is lower than previously reported. The reperfusion strategy based on pPCI was much more related to the type of admitting hospital than to the clinical characteristics of the patients. pPCI performed as suggested by the current guidelines is feasible in patients admitted in hospitals with interventional facilities available 24 hours/day, but in those who need to be transferred it is necessary to modify the existing pathways and/or treatment protocols.

[Impact of reperfusion strategies on in-hospital outcome in ST-elevation myocardial infarction in a context of interhospital network: data from the prospective VENERE registry (VENEto acute myocardial infarction REgistry]. / L'impatto delle diverse strategie riperfusive sull'esito intraospedaliero dell'infarto miocardico acuto con sopraslivellamento del tratto ST nel contesto di rete interospedaliera: studio prospettico osservazionale e multicentrico VENERE (VENEto acute myocardial infarction REgistry).

BACKGROUND: Primary angioplasty (pPCI) is the most effective reperfusion treatment of acute ST-elevation myocardial infarction (STEMI), but logistic- and organization-related problems could affect the outcome. The aim of this study was to investigate the in-hospital outcome according to reperfusion strategy in the Veneto Region cardiology network. METHODS: A treatment protocol, aimed to treat patients with high-risk STEMI by pPCI on-site or after transport, was developed and shared by the majority of cardiology departments in the Veneto Region. Data of all consecutive patients with STEMI were prospectively recorded during a 6-month period. RESULTS: 999 patients with symptom onset < 12 hours were admitted to the 28 participating hospitals: 860 were treated on-site and 139 were transferred from the admitting hospital to an interventional center for PCI. Overall, 82% of patients were treated with reperfusion therapy. Ten patients died immediately before any treatment could be initiated. In 170 patients who did not receive any reperfusion treatment, in 302 patients who received fibrinolysis (and eventually rescue PCI) and in 517 patients sent to pPCI, the following in-hospital outcome was observed respectively: mortality rate 10, 6.95 and 6.57%; reinfarction rate 0.6, 1 and 0.4%; incidence of stroke 1.7, 1.4 and 0.9%; the need for urgent revascularization procedure 6.5, 10 and 2.3%. After adjustment for confounding variables, the in-hospital occurrence of the combined events was significantly lower in patients treated with pP-CI (odds ratio 0.33, confidence interval 0.20-0.53, p < 0.01) as well as a trend for a reduced in-hospital mortality was observed (odds ratio 0.51, confidence interval 0.26-1.03, p = 0.06). CONCLUSIONS: In the VENERE registry, patients treated with pPCI had a better in-hospital outcome as compared to those treated with fibrinolytic strategy.

Immediate and midterm outcomes following primary PCI with bioresorbable vascular scaffold implantation in patients with ST-segment myocardial infarction: insights from the multicentre "Registro ABSORB Italiano" (RAI registry).

AIMS: In this multicentre prospective registry we sought to evaluate the immediate and midterm clinical outcomes following single or multiple overlapping bioresorbable vascular scaffold (BVS) implantation in the STEMI setting. METHODS AND RESULTS: A prospective cohort analysis was performed on all STEMI patients who underwent primary PCI with BVS implantation. Between December 2012 and February 2014, 1,232 STEMI patients underwent primary PCI at the participating centres. Of these, 74 (6.0%) received a BVS, 18 (24.3%) of them were multiple and overlapping. Procedural success was obtained in 72 (97.3%) cases without differences between the groups (overlapping BVS 100% vs. single BVS 96.4%, p=0.5). One patient experienced a reinfarction due to subacute BVS thrombosis which was successfully managed with balloon-only PCI while the other patient had a "slow-flow" phenomenon (final TIMI flow 2). At six-month follow-up, two non-fatal MI (2.7%), three target lesion revascularisations (4.1%), and one subacute BVS thrombosis were reported in three patients (one [5.6%] overlapping BVS and two [3.6%] in the single BVS group, p=0.5). All the events were successfully managed with re-PCI. CONCLUSIONS: BVS implantation in STEMI patients can be successfully performed with a high procedural success rate and encouraging midterm outcomes. Larger randomised trials and longer follow-up are needed to assess the potential clinical benefit of BVS versus new-generation DES in this setting.

[The heart of Italians. A population survey on the perception and evaluation of the National Health Service by citizens with heart disease and without heart disease (with special reference to cardiology)]. / Il cuore degli italiani. Indagine demoscopica sulla percezione e valutazione del Servizio Sanitario Nazionale da parte dei cittadini italiani cardiopatici e non cardiopatici (con specifico riferimento alla Cardiologia).

BACKGROUND: The purpose of this study was to collect information to understand how citizens perceive the National Health System (NHS), and what is the degree of confidence they have in the NHS. METHODS: We carried out an opinion poll with the Demos & Pi group on the perception of the NHS by Italian citizens, with particular reference to the activities related to cardiology, by interviewing 2311 people with a set of 33 questions, about the perception of their health status, lifestyles, the propensity to use public or private services, consideration of the level of the NHS, and the trust in the medical profession. The subjects included were also preliminarily stratified according to the presence or absence of heart disease. RESULTS: Overall, Italian citizens express a high level of satisfaction for the NHS (on average, 65% of approval rating), including the whole professional staff, hoping that the NHS will be kept appropriately funded. The result is even better in the subset of interviewed citizens, who suffered from cardiovascular disease. People also consider the NHS an essential requirement to ensure equity in access to medical treatment and to keep costs competitive, even compared to private healthcare. The NHS major weakness remains the waiting lists, which are considered too long for diagnostic procedures and ordinary interventions. CONCLUSIONS: There is a widespread positive feeling among Italian citizens concerning the role and functioning of the NHS. Such opinion, shared by the whole country, should be taken into account when the time will come to define strategies for health policy of the Italian society in the near future.

Clinical Comparison With Short-Term Follow-Up of Bioresorbable Vascular Scaffold Versus Everolimus-Eluting Stent in Primary Percutaneous Coronary Interventions.

Objective of this study was to assess the clinical performance of bioresorbable vascular scaffold (BVS) compared to everolimus-eluting stent (EES) in subjects with ST-segment elevation myocardial infarction (STEMI). We included all consecutive patients with STEMI who underwent percutaneous coronary intervention (PCI) with BVS implantation in centers participating to the Italian ABSORB Prospective Registry (BVS-RAI) and PCI with EES in the same centers during the same period. The 2 groups were compared. The primary end point was patient-oriented composite end point (POCE) including cardiac death, myocardial infarction, and target lesion revascularization (TLR) at the longest available follow-up. BVS or EES thrombosis at follow-up was also evaluated. Of the 563 patients with STEMI included, 122 received BVS and 441 EES. Procedural success was obtained in 549 (97.5%) cases without significant differences between the 2 groups (BVS 99.3% vs EES 97.0%, p = 0.2). At a median of 220-day (interquartile range 178 to 369) follow-up, no significant differences were observed in terms of POCE (BVS 4.9% vs EES 7.0%, p = 0.4); death (BVS 0.8%, EES 2.0%, p = 0.4), MI (BVS 4.1%, EES 2.0%, p = 0.2), TLR (BVS 4.1%, EES 4.5%, p = 0.8), device thrombosis (BVS 2.5%, EES 1.4%, p = 0.4). All TLR cases were successfully managed with re-PCI in both groups. A propensity matching of the study populations showed no significant differences regarding POCE at the longest available follow-up (odds ratio 0.53, 0.1 to 4.3). In conclusion, in this direct prospective comparison, BVS was associated with similar clinical results compared to EES in the STEMI setting. Larger and adequately powered randomized trials are needed to fully assess the potential clinical benefit of BVS versus the current standard of care in patients with STEMI.

Systematic coronary stenting after failed thrombolysis in high-risk patients with acute myocardial infarction: procedural results and long-term follow-up.

BACKGROUND: Stenting in acute myocardial infarction (AMI) represents a feasible and effective revascularization strategy. However, very little information is available for patients who receive a stent after failed thrombolysis (so-called 'rescue' stenting). METHODS: We analysed the procedural results and the 2-year follow-up of all consecutive patients with moderate-to-large AMI treated with rescue stenting in the period 1996-2001. RESULTS: The study cohort includes 123 patients (mean age 60+/-12 years, 78% men). Coronary angiography showed multivessel disease in 47% of patients; the infarct-related vessel was the left anterior descending coronary artery in 47%, the right coronary artery in 41%, the left circumflex coronary artery in 9.5% and a saphenous vein graft in 2.5%. Baseline Thrombolysis in Myocardial Infarction (TIMI) flow was grade 0-1 in 65% and grade 2 in 25%. Coronary stenting was attempted in all 123 patients and was successful in 119 out of 123 (96.7%); abciximab was used in 57 out of 123 (46%) and intra-aortic balloon pumping in 35 out of 123 (28%). At the end of the procedure, TIMI 3 flow was obtained in 104 out of 123 (85%) and TIMI 2 flow in 14 out of 123 (11%). There were 10 in-hospital deaths and four late deaths, with a long-term survival of 88.6%. This figure increases to 95.2% if patients presenting with cardiogenic shock are excluded. A new revascularization procedure was performed in 21% of discharged patients (in the target vessel for 12% and in non-target vessels for 9%). Overall, event-free survival at 2 years was 69%. At multivariate analysis, independent predictors of survival were age (P=0.014) and ejection fraction (P=0.006). CONCLUSIONS: This report represents one of the first series concerning long-term follow-up after rescue stenting. The main results include a high procedural feasibility, a low late mortality and a target vessel revascularization rate in the range expected with stenting. These data must be viewed as part of the constant effort to optimize revascularization strategies in AMI.

Predictors of right ventricular dysfunction in patients with coronary artery disease and reduced left ventricular ejection fraction.

BACKGROUND: The frequency and determinants of right ventricular (RV) dysfunction in patients with coronary artery disease (CAD) and reduced left ventricular (LV) function have not been thoroughly investigated. METHODS: The study population consists of 80 consecutive patients, invasively evaluated at our centre. Entry criteria were: LV ejection fraction < 45%; angiographic evidence of obstructive CAD; disease history of more than 3 months' duration. Exclusion criteria were: recent myocardial infarction and unstable angina. All patients underwent cardiac catheterization with coronary, LV and RV angiography. RV dysfunction was defined as a RV ejection fraction < 35%, which corresponds to the mean-three standard deviations of controls. RESULTS: Sixty-five patients (81%) had multi-vessel disease and 57 (71%) had a previous myocardial infarction. Mean LV ejection fraction was 31 +/- 8%. Mean RV ejection fraction was 46 +/- 11%. Right ventricular dysfunction was present in 14 patients (18%). An occluded proximal right coronary artery was associated with significantly lower RV ejection fraction (38 +/- 12% versus 47 +/- 10%; P = 0.009) but not LV ejection fraction (30 +/- 8% versus 32 +/- 9%; P = 0.444). However, at multivariate analysis, only pulmonary hypertension was an independent significant predictor of RV dysfunction (P < 0.001; OR: 1.13; CI: 1.06 -1.22). CONCLUSION: Right ventricular dysfunction in patients with chronic ischaemic LV dysfunction is detected in less than 20% of cases. Proximal right coronary artery occlusion is associated with a reduced RV ejection fraction. However, the role of right coronary artery disease is overwhelmed by the haemodynamic burden of pulmonary hypertension, which represents the only independent predictor of RV dysfunction in our population.

Single coronary artery associated with perimembranous ventricular septal defect.

The authors report the case of an adult male patient with a congenital ventricular septal defect who underwent an invasive assessment of his heart disease. Here, the septal defect was identified in the perimembranous area and a pulmonary-to-systemic flow ratio of 1.4:1 was calculated. At coronary angiography, a single coronary artery was found. This particular anomaly consisted of a proximal right coronary artery originating from a septal branch of the left anterior descending coronary artery and a distal right coronary artery arising from the distal left circumflex artery. Such an association constitutes an exceedingly rare congenital condition.

Effects of cardiac resynchronization therapy on disease progression in patients with congestive heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) represents a new therapeutic modality of proven efficacy for selected patients with heart failure and ventricular asynchrony. The aim of this study was to assess the effects of CRT on clinical variables and cardiac remodeling in patients with moderate-to-severe congestive heart failure and inter/intraventricular conduction delays. METHODS: Thirty-seven patients (32 males, 5 females, mean age 73 +/- 7 years), in NYHA functional class III-IV, with left ventricular ejection fraction (LVEF) < or = 35%, QRS > or = 150 ms, and left ventricular end-diastolic diameter (LVEDD) > or = 55 mm, underwent CRT by biventricular pacing (InSync, InSync III, InSync ICD; Medtronic Inc.). Fourteen (37.8%) had a previous pacemaker, and 11 (29.7%) were in permanent atrial fibrillation. The QRS width, NYHA functional class, LVEDD, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), and LVEF were retrospectively evaluated in the period before CRT. For the purposes of the present study, the pre-CRT period was divided in two: T(-2) (from 6 to 3 years) and T(-1) (from 3 years to CRT). Moreover, these parameters were measured at the time of CRT (T0) and prospectively in the post-CRT follow-up (Tp). RESULTS: Before CRT, a progressive worsening of the parameters was observed. The QRS duration steadily increased from T(-2) to T(-1) and T0 (both p = 0.000). The NYHA functional class increased from T(-2) to T(-1) and T0 (both p = 0.000). LVEDD and LVESD also increased and were higher at T(-1) (p = 0.001 and p = 0.000, respectively) and at T0 (both p = 0.000) compared to T(-2). Similar results were observed for LVEDV and LVESV. Finally, LVEF was higher at T(-2) than T(-1) and T0 (both p = 0.000). After CRT, there was a reduction in the QRS duration and an improvement in the NYHA functional class compared to T0 (both p = 0.000). LVEDD and LVESD were also reduced (p = 0.005 and p = 0.016, respectively), LVEDV and LVESV decreased (both p = 0.000), and LVEF increased (p = 0.000) with respect to T0. A highly significant correlation was found between LVEDD and LVESD both in the pre- and post-CRT time intervals, with a non-significant difference between the two linear regression lines. Similar results were obtained for the correlations between LVEDV and LVESV. CONCLUSIONS: Congestive heart failure is associated with a progressive widening of the QRS complex and a worsening of the clinical status and results in anatomic remodeling with deterioration of the left ventricular function. CRT induces opposite changes in QRS duration, clinical status, and left ventricular remodelling.

Frequency and determinants of direct stenting in routine percutaneous coronary interventions: data on 835 consecutive procedures in a single center.

BACKGROUND: Recent studies evaluated the technique of direct coronary stenting as compared to stenting-after-predilation in selected anatomic and clinical settings. However, the impact of direct stenting in routine interventional practice remains poorly elucidated. METHODS: From April 1999 to March 2001, all percutaneous coronary interventions performed at our Center were prospectively analyzed to determine the frequency of direct stenting, the success rate and the variables associated with its utilization. RESULTS: 1151 lesions were treated in 835 procedures. Stenting was attempted in 835/1151 lesions (72.5%), 309 (37%) with direct stenting and 526 (63%) with stenting-after-predilation. Direct stenting was successful in 300/309 (97%) and stenting-after-predilation in 515/526 (98%). The success rate of direct stenting was significantly lower in small vessels (< or = 2.75 mm) (89.2 vs 98.5%, p = 0.005). Patients treated with direct stenting were younger (63 +/- 11 vs 65 +/- 11 years, p = 0.024). Direct stenting was preferentially used in saphenous vein grafts and at the ostium of the left anterior descending coronary artery, while it was avoided in bifurcation lesions and with increasing calcium burden. Operators with a caseload > 140 interventions per year were significantly more likely to perform direct stenting than less experienced operators (p = 0.017). In direct stenting, the total contrast medium and the fluoroscopy and procedural times were all significantly (p < 0.0001) lower than those observed in case of stenting-after-predilation. CONCLUSIONS: Direct coronary stenting is currently performed in about one third of the overall caseload. Variables pertaining to the operator's experience, lesion morphology and length, vessel size, and the clinical presentation are all important factors determining the selection of candidates suitable for direct stenting.

[Coronary angioplasty in subgroups at risk: patients treated with bypass]. / L'angioplastica coronarica in sottogruppi a rischio: gli operati di bypass.

Percutaneous coronary intervention represents an established method to obtain revascularization in patients suffering from obstructive coronary artery disease. Despite the predictability of procedural results and the favorable clinical outcome shown in large series, there are still areas in which the clinical benefits of intervention are less impressive and a lot remains to be done to improve both procedural and clinical outcomes. Among these areas, one may well include the subgroup of patients with previous bypass surgery, who have been consistently shown to be affected by a high rate of periprocedural complications as well as late recurrence. The risk profile of these patients is examined under two main perspectives: the burden of more severe baseline clinical conditions (age, ventricular function, severity of coronary disease) and the negative impact of graft atherosclerosis. The basic assumption of this article is that a variable combination of these characteristics identifies subsets with increasing risk of complications and/or recurrence. For this reason, results of percutaneous revascularization in these patients may still represent a technical as well as a clinical challenge. In particular, the long debated relationship between composition of atherosclerotic plaque in saphenous vein graft, distal embolization, periprocedural myocardial damage and early and late adverse events represents a negative sequence that currently available pharmacologic and interventional resources cannot consistently antagonize. Added to this, are the unresolved issues of diffuse degeneration and chronic total occlusion of saphenous vein grafts, in which no therapeutic approach, alone or in combination, has substantially modified the poor outcome of these lesions. The use of glycoprotein IIb/IIIa receptor antagonists is also discussed, in the light of available data derived from large clinical trials, casting doubts on the efficacy of these otherwise essential pharmacologic agents. Lastly, the setting of acute myocardial infarction represents the clinical scenario in which the adverse effects of the combination of clinical and angiographic characteristics are clearly appreciated. Both coronary intervention and cardiac surgery represent fields of rapidly growing knowledge and technology. It is likely that in the near future we will witness major changes in the clinical management of these patients, thanks to the increasing utilization of arterial conduits, the widespread use of local drug delivery, the availability of new percutaneous devices, and the development of integrated pharmacologic and mechanical revascularization strategies.

[Combination therapy for acute myocardial infarction with glycoprotein IIb/IIIa inhibitors and fibrinolysis]. / Infarto miocardico acuto ST sopra: associazione tra inibitori delle glicoproteine e trombolitico? Pareri a confronto.

The best conventional fibrinolytic regimens succeed in restoring unimpeded coronary flow (i.e., TIMI grade 3 reperfusion) in only about 50% of lytic-eligible patients. In experienced hands, percutaneous coronary intervention (angioplasty + stent implantation) can restore TIMI 3 flow in more than 80% of patients; however, it is not universally available, and usually cannot be performed as promptly as fibrinolytic therapy. Researchers now recognize that one key reason fibrinolytic therapy fails is that it does not adequately address the role of platelets in both the initial formation and posttreatment recurrence of coronary thrombus activated, aggregating platelets at the site of plaque fissure or rupture form the core ("white" clot) of an intracoronary thrombus. The platelets contribute to the further development of a meshwork of fibrin, thrombin, and entrapped blood cells ("red" clot), which usually makes up the bulk of an occlusive coronary thrombus. Plasminogen activators, such as alteplase and reteplase, lyse fibrin in the red thrombus but leave the platelet-rich core intact. The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban, and eptifibatide bind to GP IIb/IIIa receptors on the surfaces of activated platelets. By preventing the receptors from binding to fibrinogen (and, hence, to each other) GP IIb/IIIa inhibitors block the "final common pathway" to platelet aggregation. Combining fibrinolysis with GP IIb/IIIa blockade to treat acute myocardial infarction could, theoretically, yield a number of benefits. It would attack both red and white components of the occlusive thrombus, help suppress the thrombotic rebound effect of fibrinolytics by preventing platelet activation in response to newly exposed thrombin, improve reperfusion and microvascular flow, reduce the incidence of postfibrinolytic hemorrhagic stroke (currently approximately 1%) if combination therapy permits use of lower dosages of fibrinolytic agents. Two phase II trials of fibrinolytic therapy plus GP IIb/IIIa blockade have recently been reported. In TIMI 14, the reduced-dose combinations of alteplase plus abciximab produced TIMI 3 rates higher than the control group. In the TIMI 14 reteplase substudy, TIMI 3 flow rates with reteplase at 90 min was 70% for standard dose reteplase alone, 70% for reteplase 5 IU + 5 IU plus abciximab, and 77% for reteplase 10 IU + 5 IU plus abciximab. In the SPEED pilot study the highest TIMI 3 rates was seen with the regimen of 5 IU + 5 IU double-bolus reteplase plus abciximab (54 vs 47%). The findings of both the SPEED and TIMI 14 trials were incorporated into the design of the large (approximately 17,000 patients) GUSTO V mortality trial, which compared standard reteplase therapy with abciximab plus low-dose reteplase. Unfortunately, the results did not confirm the favorable angiographic findings of the phase II trials reported above, because the two strategies showed the same mortality rate at 30-day follow-up. The present review will try to shed light on the "dark side of the moon" of the association between IIb/IIIa inhibitors and fibrinolytic drugs in order to understand the unexpected GUSTO V results, now matched by the ASSENT-3 disappointing results with tenecteplase plus abciximab.

Renal denervation: intractable hypertension and beyond.

BACKGROUND: Hypertension continues to be a major burden of public health concern despite the recent advances and proven benefit of pharmacological therapy. A certain subset of patients has hypertension resistant to maximal medical therapy and appropriate lifestyle measures. A novel catheter-based technique for renal denervation (RDN) as a new therapeutic avenue has great promise for the treatment of refractory hypertension. SUMMARY: This review included the physiology of the renal sympathetic nervous system and the renal nerve anatomy. Furthermore, the RDN procedure, technology systems, and RDN clinical trials as well as findings besides antihypertensive effects were discussed. Findings on safety and efficacy seem to suggest that renal sympathetic denervation could be of therapeutic benefit in refractory hypertensive patients. Despite the fast pace of development in RDN therapies, only initial and very limited clinical data are available. Large gaps in knowledge concerning the long-term effects and consequences of RDN still exist, and solid, randomized data are warranted.

Outcome of patients on oral anticoagulation undergoing coronary artery stenting: data from discharge to 12 months in the Warfarin and Coronary Stenting (WAR-STENT) Registry.

OBJECTIVES: To obtain further, and more focused, information on the efficacy and safety of the antithrombotic regimens, including triple therapy (TT) of warfarin, aspirin, and clopidogrel; dual therapy (DT) of warfarin and single antiplatelet agent (aspirin or clopidogrel); and dual-antiplatelet therapy (DAPT) of aspirin and clopidogrel, prescribed to patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S). BACKGROUND: The true efficacy and safety of TT, DT, and DAPT in OAC patients undergoing PCI-S is largely undefined. METHODS: We analyzed the database of the prospective, multicenter WARfarin and coronary STENTing (WAR-STENT) registry (ClinicalTrials.gov identifier NCT00722319), only including the post-discharge period. RESULTS: Of the 401 patients discharged alive from index hospitalization, 339 (85%), 20 (5%), and 42 (10%) were prescribed TT, DT, and DAPT, respectively. Throughout a mean follow-up of 368.3 ± 22.8 days, major adverse cardiovascular events (MACE) (including cardiovascular death, myocardial infarction, repeat revascularization, stent thrombosis, and thromboembolism), total bleeding, major bleeding, and combination of MACE plus total bleeding were comparable across the three treatment groups. The absolute rate of major bleeding with TT was 4%. The antithrombotic treatment actually ongoing at major bleeding was TT in 44%, DT in 50%, and DAPT in 6% of cases. CONCLUSION: In the real-world population of OAC patients undergoing PCI-S in the WAR-STENT registry, the three antithrombotic regimens of TT, DT, and DAPT showed comparable efficacy and safety. Due to several limitations, our data cannot be considered conclusive in confuting the current recommendations to prescribe TT. Further properly designed and sized studies are warranted.

Clinical outcome of patients with de novo coronary bifurcation lesions treated with the Tryton Side Branch Stent. The SAFE-TRY prospective multicenter single arm study.

BACKGROUND: Coronary bifurcation lesions represent a difficult problem regularly confronting interventional cardiologist, in part due to the lack of dedicated device. OBJECTIVE: To investigate the feasibility, safety and effectiveness of the Tryton Side Branch Stent (Tryton Medical, Durham, NC, USA), a dedicated bare metal stent deployed in conjunction with a standard drug-eluting stent to treat bifurcation lesions. METHODS: The SAFE-TRY is a prospective single arm multicenter registry including patients with de novo bifurcation lesions in native coronary arteries and syntax score <32. The primary endpoint was target vessel failure (TVF) at 30 days that comprised cardiac death, target vessel myocardial infarction and clinically driven target vessel revascularization. Secondary endpoints included device, angiographic and procedural success, 9-month major adverse cardiac and cerebrovascular event (MACCE), and stent thrombosis (ST) rates (ClinicalTrials.gov identifier: NCT01174433). RESULTS: Among 252 enrolled patients, 24% had diabetes and 35.3% unstable angina. True bifurcation lesions involving both branches occurred in 96.8% of cases with Medina classification 1.1.1 in 62%. The left anterior descending artery and the left main were treated in 70% and 8.3% of the patients, respectively. A 6 Fr guide catheter was used in 61% of the cases. Device, angiographic and procedural success rates were 99.6%, 99.6% and 97.2% respectively. The 30-day TVF was 2.8%; the 9-month MACCE rate was 13.7%, with target lesion revascularization being 4.4%. No definite ST occurred. CONCLUSIONS: This prospective, multicenter study confirmed the feasibility, safety and effectiveness of the Tryton Side Branch Stent to treat patients with de novo complex bifurcation lesions.