[Costs of healthcare resource consumption after a myocardial infarction in France: An estimate from a medicoadministrative database (GSB)]. / Coût des consommations de soins après un infarctus du myocarde en France : une estimation à partir de l'échantillon généraliste des bénéficiaires (EGB).

OBJECTIVE: To estimate the costs of healthcare resource consumption in the year preceding and the year following a myocardial infarction (MI). PATIENTS AND METHODS: A historical cohort of patients experiencing an MI in France between 2007 and 2011 was extracted from the échantillon généraliste de bénéficiaires, a 1/97th sample of all beneficiaries of public health insurance in France. RESULTS: A total of 1920 patients experiencing an MI were identified. Two-thirds were men and the mean age was 67 years; 20.6% had diabetes, 37.6% hypercholesterolaemia and 82.4% hypertension. From a societal perspective, the annual costs of medical consumption related to hospitalisations increased from € 4548 before the MI to € 6470 in the following year. Costs of community care rose from € 2932 to € 6208. This increase concerned all components of community healthcare: costs associated with medical transportation increased fourfold, those associated with consultations and laboratory tests tripled, medication costs doubled and costs of paramedical services also increased, but to a lesser extent. It should be noted that the cost of hospitalisation for the index MI (€ 5876) is not included in the above costs. CONCLUSION: From a society perspective, the cost of healthcare resource consumption increased threefold in the year following an MI.

Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach.

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).

Consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome.

The Diabetes and Cardiovascular Disease study group of the Société francophone du diabète (SFD, French Society of Diabetes) in collaboration with the Société française de cardiologie (SFC, French Society of Cardiology) have devised a consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome (ACS); in particular, it includes the different phases of ACS [the intensive care unit (ICU) period, the post-ICU period and the short-term follow-up period after discharge, including cardiac rehabilitation] and also embraces all of the various diagnostic and therapeutic issues with a view to optimizing the collaboration between cardiologists and diabetologists. As regards diagnosis, subjects with HbA(1c) greater or equal to 6.5% on admission may be considered diabetic while, in those with no known diabetes and HbA(1c) less than 6.5%, it is recommended that an OGTT be performed 7 to 28 days after ACS. During hospitalization in the ICU, continuous insulin treatment should be initiated in all patients when admission blood glucose levels are greater or equal to 180 mg/dL (10.0 mmol/L) and, in those with previously known diabetes, when preprandial glucose levels are greater or equal to 140 mg/dL (7.77 mmol/L) during follow-up. The recommended blood glucose target is 140-180 mg/dL (7.7-10 mmol/L) for most patients. Following the ICU period, insulin treatment is not mandatory for every patient, and other antidiabetic treatments may be considered, with the choice of optimal treatment depending on the metabolic profile of the patient. Patients should be referred to a diabetologist before discharge from hospital in cases of unknown diabetes diagnosed during ACS hospitalization, of HbA(1c) greater or equal to 8% at the time of admission, or newly introduced insulin therapy or severe/repeated hypoglycaemia. Referral to a diabetologist after hospital discharge is recommended if diabetes is diagnosed by the OGTT, or during cardiac rehabilitation in cases of uncontrolled diabetes (HbA(1c) ≥ 8%) or severe/repeated hypoglycaemia.

Consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome.

The Diabetes and Cardiovascular Disease study group of the Société francophone du diabète (SFD, French Society of Diabetes) in collaboration with the Société française de cardiologie (SFC, French Society of Cardiology) have devised a consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome (ACS); in particular, it includes the different phases of ACS [the intensive care unit (ICU) period, the post-ICU period and the short-term follow-up period after discharge, including cardiac rehabilitation] and also embraces all of the various diagnostic and therapeutic issues with a view to optimalizing the collaboration between cardiologists and diabetologists. As regards diagnosis, subjects with HbA(1c) greater or equal to 6.5% on admission may be considered diabetic while, in those with no known diabetes and HbA(1c) less than 6.5%, it is recommended that an OGTT be performed 7 to 28days after ACS. During hospitalization in the ICU, continuous insulin treatment should be initiated in all patients when admission blood glucose levels are greater or equal to 180mg/dL (10.0mmol/L) and, in those with previously known diabetes, when preprandial glucose levels are greater or equal to 140mg/dL (7.77mmol/L) during follow-up. The recommended blood glucose target is 140-180mg/dL (7.7-10mmol/L) for most patients. Following the ICU period, insulin treatment is not mandatory for every patient, and other antidiabetic treatments may be considered, with the choice of optimal treatment depending on the metabolic profile of the patient. Patients should be referred to a diabetologist before discharge from hospital in cases of unknown diabetes diagnosed during ACS hospitalization, of HbA(1c) greater or equal to 8% at the time of admission, or newly introduced insulin therapy or severe/repeated hypoglycaemia. Referral to a diabetologist after hospital discharge is recommended if diabetes is diagnosed by the OGTT, or during cardiac rehabilitation in cases of uncontrolled diabetes (HbA(1c)≥8%) or severe/repeated hypoglycaemia.

Oral antiplatelet agents in ACS: from pharmacology to clinical differences.

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.

REACH: international prospective observational registry in patients at risk of atherothrombotic events. Results for the French arm at baseline and one year.

INTRODUCTION: Atherothrombosis is a systemic, diffuse disease associated with a high risk of cardiovascular morbidity and mortality. It is the main cause of death in Western populations, a major public health concern and its prevalence will further increase in the future. OBJECTIVES: To evaluate the rate of major vascular events at 1 year in French patients with confirmed atherothrombotic disease, recruited in the REACH international registry. METHODS: The REACH Registry has recruited 55.000 patients in 44 countries, aged at least 45 years and suffering from established atherothrombotic disease (EAD). In France, 713 investigators selected 3.514 patients with EAD between December 2003 and June 2004. Each investigator had to include 5 to 10 patients presenting after a first documented event of cerebrovascular disease (CVD), coronary artery disease (CAD) or lower limb peripheral arterial occlusive disease (PAD). The patients were followed up for 1 year with collection of major vascular events. RESULTS: Among the 3514 French patients with EAD in the REACH registry, 2.373 (68%) had documented coronary disease, 778 (22%) had an ischemic stroke and 923 (26%) had documented PAD. One quarter of CAD patients, one third of CVD patients and one half of PAD patients had another atherothrombotic disease localization. Follow-up at 1 year was documented for 3.373 patients with EAD. The 1-year event rate in patients who had EAD was a function of the number of atherothrombotic localizations: the vascular death rate was 1.8% if there was a single localization and 4.1% if there were 2 or 3 localizations, and the composite death, infarct and stroke rates were 3.8% and 7.2% respectively and 11.7% and 22.3% respectively if hospitalizations were added to the latter endpoint. CONCLUSION: The number of major vascular events during the first year is high in EAD patients although these patients were followed up on an outpatient basis and are considered to be stable. In patients with prior EAD, there was a close link between the incidence of major vascular events and the number of symptomatic arterial beds (2 or 3 sites). The risk of a major vascular event was twice as high in patients with polyvascular involvement than in those who only had one affected artery.

Load force during manual transport in Parkinson's disease.

OBJECTIVES: To search for a physiological method for the measurement of upper extremity dexterity during activities of daily life in Parkinson's disease (PD). MATERIALS AND METHODS: We examined load force output during manual transport in seven patients with PD and 10 healthy controls. PD patients were measured in both the non-medicated and medicated states. The test movement included two continuous sub-movements: an upward-forward transport of an object from the table to the stand, and a downward-backward transport of the object from the stand to the table. Hand movements were recorded using an optoelectronic camera, and load force was measured using a force sensor installed in the test object. RESULTS: Compared with the controls, PD patients had a different pattern of load force output characterized by slower force development and release, lower peak force, and less dynamic force generation during movement. After medication, the speed of force development and the level of peak force increased in the patients. CONCLUSIONS: These findings suggest that PD impairs the production of preprogrammed movements. The movements observed in the PD patients may result from compensatory strategies relying more on feedback mechanisms.

The ENACT study: a pan-European survey of acute coronary syndromes. European Network for Acute Coronary Treatment.

AIM: The European Network for Acute Coronary Treatment (ENACT) study was designed to collect prospective information across Europe on the relative frequency, diagnosis and management of the whole spectrum of acute coronary syndromes. METHODS: Cardiologists, who were respondents to mailings sent out to 17 European countries with the target of reaching one centre per million inhabitants, completed a prospective patient record, each physician providing information on 10 consecutive patients with a working diagnosis on admission of acute coronary syndrome, and a questionnaire. RESULTS: A total of 390 responses were received (0.91/10(6)population) with data on 3092 patients in 29 countries. The patient population comprised 1431 (46%) with an initial working diagnosis of unstable angina/non-ST-segment elevation myocardial infarction, 1205 (39%) with myocardial infarction and 445 (14%) with suspected acute coronary syndrome. The ratio of unstable angina to myocardial infarction was 1.2:1 and this was similar across Europe. An initial diagnosis of myocardial infarction was more likely to be confirmed than unstable angina or suspected acute coronary syndrome. There were wide variations in the rates of angiography and percutaneous coronary intervention across Europe. Most unstable angina patients received aspirin, nitrates and heparin (unfractionated heparin 44% intravenous, 16% subcutaneous; low-molecular-weight heparin 50%). Overall, 50% of unstable angina patients and 34% of myocardial infarction patients received low-molecular-weight heparin and 6% and 8% respectively received a glycoprotein IIb/IIIa inhibitor, but there were large inter-country differences. There were also national differences in the use of calcium antagonists, angiotensin-converting enzyme inhibitors and beta-blockers. CONCLUSION: The ENACT study provides robust data, for the first time, on the relative frequency of unstable angina and acute myocardial infarction across Europe. It provides insight into differences in management across Europe and a reference benchmark of current treatment.

Reperfusion syndrome: relationship of coronary blood flow reserve to left ventricular function and infarct size.

OBJECTIVES: We tested the hypothesis that the reperfusion syndrome (RS), defined as an additional elevation of the ST segment upon reperfusion, may be a marker of microcirculatory reperfusion injury during acute myocardial infarction (AMI). BACKGROUND: The pathophysiology of the RS is unknown, and its prognostic implications are controversial. METHODS: Twenty-one patients with an anterior AMI treated < or =12 h after onset by primary coronary angioplasty (PTCA) were studied. Coronary velocity reserve (CVR), an index of microcirculatory function, was measured using a Doppler guidewire. Left ventricular (LV) ejection fraction, infarct size (percent defect) and LV end-systolic volume index (LVESVi) were evaluated by radionuclide ventriculography, 201T1 single-photon emission computed tomography and contrast ventriculography, respectively. RESULTS: Baseline ST elevation and pain-to-TIMI 3 time were similar in patients with and without RS. Patients with RS (10/21) had a lower post-PTCA CVR than patients without RS (median [95% confidence interval]: 1.2 [1-1.3] vs. 1.6 [1.5-1.7], p < 0.005). Even though predischarge CVR was similar in the two groups, infarct size at six weeks (26 [21 to 37] vs. 14 [10-17]% 201T1 defect, p = 0.001) and predischarge LVESVi (45% [40 to 52] vs. 30% [29 to 38] mL/m2, p = 0.001) were larger, and LV ejection fraction at six weeks (40% [37 to 46] vs. 55% [50 to 60], p = 0.004) was lower in patients with RS than in patients without RS. CONCLUSIONS: Patients with RS during primary PTCA for an anterior AMI have a transiently lower CVR than patients without RS, but sustained LV dysfunction and larger infarct size, suggesting that RS is a marker of microcirculatory reperfusion injury.

Relationship between resting 201Tl reverse redistribution, microvascular perfusion, and functional recovery in acute myocardial infarction.

UNLABELLED: 201TI reverse redistribution is a common finding early after reperfusion therapy for myocardial infarction. Its mechanism and clinical implications remain unclear. The aim of this study was to clarify the relationships between reverse redistribution, microvascular perfusion, and myocardial viability. METHODS: Resting, 10-min-postinjection, and redistribution 201TI data obtained for 33 patients 8 and 42 d after the onset of acute myocardial infarction were compared with echocardiographic wall motion measured acutely and on day 42. Microvascular perfusion was assessed by myocardial contrast echocardiography performed 10 min after restoration of complete patency of the infarct artery. RESULTS: Marked significant reverse redistribution was found on day 8 (absolute change, 7.5%+/-7.9% of the 10-min-postinjection defect size; P<5x0.000001) and significantly decreased on day 42 (2.7%+/-6.8%; P = 0.004 between days 8 and 42). The 10-min-postinjection defect size best predicted the final infarct size on day 42 and was closely related to microvascular perfusion. Patients with adequate reperfusion had a smaller postinjection defect on day 8 (21.1%+/-14.6%) and a larger reverse redistribution (10.2%+/-6.1%) than did patients with no reflow (35.3%+/-13% and 3.2%+/-9.2%, respectively; P<0.04 for both). CONCLUSION: Reverse redistribution was marked early after myocardial infarction in patients with complete patency of the infarct artery and decreased in subsequent weeks. Reverse redistribution was associated with restoration of adequate microvascular reperfusion and with myocardial salvage and viability. The early postinjection scans on day 8 were the relevant images for assessing myocardial salvage and predicting wall motion recovery.

Involvement of the endothelin system in experimental critical hind limb ischemia.

BACKGROUND: Endothelin- (ET-1) is involved in the pathogenesis of several ischemic diseases. We investigated the hypotheses that ET-1 is involved in the pathogenesis of experimental critical hind limb ischemia and that ET-1 receptor antagonists have a protective effect. MATERIALS AND METHODS: Critical hind limb ischemia was achieved by exclusion of the femoral artery and embolization of collateral vessels in rats. The induction of endothelin system components by ischemia was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) (mRNAs) and immunoassay (peptides) in the plasma and ischemic muscles 5 hr (H5), 5 days (D5) and 14 days (D14) after ischemia. Two groups of rats received 100 mg/kg/day of either Bosentan, a mixed ET(A/B) receptor antagonist (n = 12), or LU 135252, a selective ET(A) receptor antagonist (n = 9), and a control group without treatment (n = 12) served as control. Muscle blood flow and ischemia were monitored in the ischemic limb by laser Doppler and phosphorylase activity, respectively. RESULTS: The procedure induced an 80% decrease in muscle blood flow and complete suppression of phosphorylase activity without necrosis. At day 14, the tissue blood flow remained reduced by 70% and phosphorylase activity was suppressed completely. There was up-regulation of preproendothelin-1, preproET-3, endothelin converting enzyme-1, and ET(A). ET(B) receptor mRNAs in ischemic muscle at day 5 and day 14 was accompanied by an increase in muscle concentration of ET-1 at day 5, without significant changes in plasma endothelin. Treatment with Bosentan and LU 135252 increased tissue blood flow and reduced muscle ischemia at day 14. CONCLUSIONS: Tissue production of ET- 1 is up-regulated in experimental critical hind limb ischemia. Inhibition of the endothelin system by a mixed ET(A/B) receptor antagonist may protect, at least in part, against muscle injury.

Catheter-based reperfusion of unprotected left main stenosis during an acute myocardial infarction (the ULTIMA experience). Unprotected Left Main Trunk Intervention Multi-center Assessment.

The ULTIMA registry was a prospective, multicenter, international registry of 277 patients who underwent percutaneous coronary interventions of unprotected left main trunk stenosis. The 40 patients who underwent an emergency percutaneous left main intervention for acute myocardial infarction are the focus of this study. We compared the results of primary angioplasty with primary stenting, characterizing both the short-term (in-hospital) and long-term (12-month) outcomes. Of the 40 patients, 23 underwent primary angioplasty, whereas 17 underwent primary stenting. The angiographic success rate was an 88% for the cohort. The in-hospital death or coronary artery bypass grafting rate was 65% for the entire group, 74% for the percutaneous transluminal coronary angioplasty group (PTCA), and 53% for the stent group (p = 0.2). The in-hospital death rate was 55% for the entire cohort, 70% for the PTCA group, and 35% for the stent group (p = 0.1). The 12-month rate of death or bypass surgery was 83% and 58% for the PTCA and stent groups, respectively (p = 0.047). The 12-month survival rate was 35% and 53% for the PTCA and stent groups, respectively (p = 0.18). Bypass surgery was required in 6 patients in the PTCA group and 2 patients in the stent group (p = 0.07). Patients undergoing percutaneous interventions for unprotected left main myocardial stenosis during an acute myocardial infarction are critically ill; an initial percutaneous revascularization approach appears feasible and may be the preferred revascularization strategy. Primary stenting was associated with improved clinical outcomes.

NC100100, a new echo contrast agent for the assessment of myocardial perfusion--safety and comparison with technetium-99m sestamibi single-photon emission computed tomography in a randomized multicenter study.

BACKGROUND AND HYPOTHESIS: Myocardial contrast echocardiography using second-generation agents has been proposed to study myocardial perfusion. A placebo-controlled, multicenter trial was conducted to evaluate the safety, optimal dose, and imaging mode for NC100100, a novel intravenous second-generation echo contrast agent, and to compare this technique with technetium-99m sestamibi (MIBI) single-photon emission computed tomography (SPECT). METHODS: In a placebo-controlled, multicenter trial, 203 patients with myocardial infarction > 5 days and < 1 year previously underwent rest SPECT and MCE. Fundamental and harmonic imaging modes combined with continuous and electrocardiogram-- (ECG) triggered intermittent imaging were used. Six dose groups (0.030, 0.100, and 0.300 microliter particles/kg body weight for fundamental imaging; and 0.006, 0.030, and 0.150 microliter particles/kg body weight for harmonic imaging) were tested. A saline group was also included. Safety was followed for 72 h after contrast injection. Myocardial perfusion by MCE was compared with myocardial rest perfusion imaging using MIBI as a tracer. RESULTS: NC100100 was well tolerated. No serious adverse events or deaths occurred. No clinically relevant changes in vital signs, laboratory parameters, and ECG recordings were noted. There was no significant difference between adverse events in the NC100100 (25.7%) and in the placebo group (17.9%, p = 0.3). Intermittent harmonic imaging using the intermediate dose was superior to all other modalities, allowing the assessment of perfusion in 76% of all segments. Eighty segments (96%) with normal perfusion by SPECT imaging also showed myocardial perfusion with MCE. However, a substantial percentage of segments (61-80%) with perfusion defects by SPECT imaging also showed opacification by MCE. This resulted in an overall agreement of 66-81% and a high specificity (80-96%), but in low sensitivity (20-39%) of MCE for the detection of perfusion defects. CONCLUSION: NC100100 is safe in patients with myocardial infarction. Intermittent harmonic imaging with a dose of 0.03 microliter particles/kg body weight can be proposed as the best imaging protocol. Myocardial contrast echocardiography with NC 100100 provides perfusion information in approximately 76% of segments and results in myocardial opacification in the vast majority of segments with normal perfusion as assessed by SPECT. Although the discrepancies between MCE and SPECT with regard to the definition of perfusion defects requires further investigation, MCE with NC 100100 is a promising technique for the noninvasive assessment of myocardial perfusion.

Permanent Electronic Storage of Angiographic Images in the Catheterization Laboratory: High-Resolution and Real-Time Acquisition on Optical Laserdiscs.

The use of electronic ÒfilmlessÓ media for long-term archiving of coronary angiograms has been impeded by the problems of image storage and data transfer among institutions. Although long-term analogue storage of the images is presently feasible, and much less costly than digital storage, processing has been limited to a 625 lines video format, not optimal for high quality images. We developed a bi-directional 1249/625 lines converter, able to store and to replay high resolution (1249 lines) video images, from Component Record Video (CRV) Optical Laser (Analogue) Videodisks. Image quality and medical relevance were evaluated five ways: 1) Outside experts compared 593 static images stored on CRV discs to the same images stored in a high-resolution digital format blinded to source of image. The four experts found no visual or medical difference in 98% of evaluated images and minor differences in the remainder. The differences in the remaining images were not consistent among experts. 2) Two of the experts also compared the enhanced CRV optically stored image to the image obtained on simultaneously recorded 35mm cine film, and found the enhanced CRV stored image to be superior or similar, but never inferior to the film image. 3) 90 representatives from 63 outside institutions compared images from both a digital hard drive and the enhanced CRV optical (analogue) storage displayed at a Windows based digital workstation. During the test they were blinded as to the source of the images. The representatives found no difference in image resolution, quality, diagnostic accuracy, and medical relevance. 4) We evaluated quantitative coronary angiography (QCA) on standard coronary test phantoms using enhanced CRV stored images digitally processed. The correlation of the enhanced CRV image to the actual size of the phantom vessels was similar to the results obtained in the literature from digitally stored images. 5) 78 arterial measurements ranging 0.65 to 4.85 mm were evaluated both from the digital hard disc (D) and the CRV optical disc (CRV), using the same QCA analytical package. The correlation coefficient and the Standard Error of the Estimate between D and CRV values were respectively 0.997 and 0.076, no systematic over or underestimation occurred, and the mean variability was inferior to 0.1 mm. CONCLUSION: High-Resolution CRV-optical storage represents a cost-effective solution for excellent image quality equivalent to digitally stored images, permitting permanent electronic archiving inside the cath-lab, and allowing digital image processing and digital image communication.

Optimal techniques for arterial gene transfer.

Cardiovascular gene therapy is becoming a clinical reality due to improved vectors, delivery systems and careful experimental validation studies. Nearly all cardiovascular diseases are amenable to gene therapy, but the optimal combination of vector, delivery system and therapeutic gene is likely to be unique to each application. Currently, the most efficient vectors available are replication-defective adenoviral vectors, but transgene expression is limited in time due to a strong immune response. Conversely, non-viral vectors or plasmid DNA may be used safely but have very limited efficiency. Percutaneous, catheter-based delivery is feasible for most applications. The ultimate issues that will decide of the future of gene therapy are safety of the transfer and delivery techniques as well as cost/effectiveness comparisons with alternative therapies, including local delivery of drugs, proteins and/or mechanical devices.

Percutaneous delivery of the gax gene inhibits vessel stenosis in a rabbit model of balloon angioplasty.

OBJECTIVES: The expression of gax, an anti-proliferative homeobox gene, is rapidly downregulated in vascular smooth muscle cells (VSMCs) following arterial injury. Here we performed percutaneous adenovirus-mediated gene transfer into the iliac arteries of normal rabbits using a channel balloon catheter to assess the effects of gax overexpression on neointima formation, lumen diameter, reendothelialization and functional vasomotion. METHODS: A channel balloon catheter was used to perform both the arterial injury and local gene delivery. In each animal both iliac arteries were randomly assigned to receive either an adenovirus expressing the gax gene (Ad-Gax) or the beta-galactosidase gene (Ad-beta gal). In a second group of animals arteries were randomly assigned to receive either Ad-beta gal or saline. RESULTS: At one month, angiography revealed 36% less luminal narrowing in the Ad-Gax-treated arteries relative to the Ad-beta gal-treated control arteries. Histological analysis revealed that the intimal/medial ratio (I/M) was reduced by 56% in the Ad-Gax group. Endothelium-dependent vasomotion was not affected by the gax gene transfer. In the second group, no statistically significant differences were found between the saline and the Ad-beta gal-treated vessels for any of these parameters. CONCLUSIONS: Percutaneous adenovirus delivery of the gax gene to rabbit iliac arteries following endothelial denudation and vessel wall injury reduces neointimal hyperplasia and luminal stenosis, but does not affect endothelium-dependent vasomotion. This study demonstrates that a VSMC transcription factor can potentially be utilized for the development of a molecular therapy for vascular disorders.

Radial access for primary PTCA in patients with acute myocardial infarction and contraindication or impossible femoral access.

We report two cases of acute myocardial infarction treated by primary percutaneous transluminal coronary angioplasty (PTCA) in which femoral arterial access was either contraindicated or impossible. In both, emergency PTCA was successfully performed via the left radial artery. Including stent implantation in one patient, without entry site complication.

Perspectives of arterial gene therapy for the prevention of restenosis.

Restenosis remains the main limitation of interventional cardiology. Restenosis is an important target for gene therapy since it is frequent (30% of patients), costly (estimated $2 billion annually), refractory to all pharmacological therapies, and related, at least in part, to smooth muscle cell proliferation which is an inviting target for antiproliferative molecular strategies. Because cell division is ultimately controlled by intranuclear events, the protein product of genes selected for their antiproliferative effects usually remains inside the cells. Consequently, the transfer of growth-inhibitory genes needs to be efficient-i.e., involve a large proportion of smooth muscle cells populating the angioplasty site. To date, adenoviral vectors are, by far, the most efficient vectors to perform in vivo arterial gene delivery. These vectors, as well as others, have been recently used to demonstrate that therapeutic genes encoding cytolytic (thymidine kinase) or cytostatic (hypophosphorylatable retinoblastoma protein, endothelial nitric oxide synthase, gax, etc.) products successfully inhibit smooth muscle cell proliferation and related intimal hyperplasia. Despite substantial progress, major technical issues remain to be addressed before gene therapy is applied to clinical restenosis. First-generation recombinant adenoviruses evoke both cellular and humoral immune responses leading to local toxicity and transient gene expression. Moreover, the low efficiency of gene transfer to atherosclerotic arteries may further impair the biological effect of antiproliferative genes. Finally, restenosis is a multifactorial phenomenon in which intimal hyperplasia plays an important but not exclusive role. Prevention of constrictive remodeling should also be taken into account in an integrated genetic strategy to prevent restenosis.