The dynamic TRPV2 ion channel proximity proteome reveals functional links of calcium flux with cellular adhesion factors NCAM and L1CAM in neurite outgrowth.

TRPV2 voltage-insensitive, calcium-permeable ion channels play important roles in cancer progression, immune response, and neuronal development. Despite TRPV2's physiological impact, underlying endogenous proteins mediating TRPV2 responses and affected signaling pathways remain elusive. Using quantitative peroxidase-catalyzed (APEX2) proximity proteomics we uncover dynamic changes in the TRPV2-proximal proteome and identify calcium signaling and cell adhesion factors recruited to the molecular channel neighborhood in response to activation. Quantitative TRPV2 proximity proteomics further revealed activation-induced enrichment of protein clusters with biological functions in neural and cellular projection. We demonstrate a functional connection between TRPV2 and the neural immunoglobulin cell adhesion molecules NCAM and L1CAM. NCAM and L1CAM stimulation robustly induces TRPV2 [Ca2+]I flux in neuronal PC12 cells and this TRPV2-specific [Ca2+]I flux requires activation of the protein kinase PKCα. TRPV2 expression directly impacts neurite lengths that are modulated by NCAM or L1CAM stimulation. Hence, TRPV2's calcium signaling plays a previously undescribed, yet vital role in cell adhesion, and TRPV2 calcium flux and neurite development are intricately linked via NCAM and L1CAM cell adhesion proteins.

Structural insights into TRPV2 activation by small molecules.

Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators.

Sequential Combination of Cognitive-Behavioral Treatment and Well-Being Therapy in Depressed Patients with Acute Coronary Syndromes: A Randomized Controlled Trial (TREATED-ACS Study).

INTRODUCTION: Randomized controlled trials (RCT) of psychotherapeutic interventions have addressed depression and demoralization associated with acute coronary syndromes (ACS). The present trial introduces psychological well-being, an increasingly recognized factor in cardiovascular health, as a therapeutic target. OBJECTIVE: This study was designed to determine whether the sequential combination of cognitive-behavioral therapy (CBT) and well-being therapy (WBT) may yield more favorable outcomes than an active control group (clinical management; CM) and to identify subgroups of patients at greater risk for cardiac negative outcomes. METHODS: This multicenter RCT comparedCBT/WBT sequential combination versus CM, with up to 30 months of follow-up. One hundred consecutive depressed and/or demoralized patients (out of 740 initially screened by cardiologists after a first episode of ACS) were randomized to CBT/WBT associated with lifestyle suggestions (n = 50) and CM (n = 50). The main outcome measures included: severity of depressive symptoms according to the Clinical Interview for Depression, changes in subclinical psychological distress, well-being, and biomarkers, and medical complications and events. RESULTS: CBT/WBT sequential combination was associated with a significant improvement in depressive symptoms compared to CM. In both groups, the benefits persisted at follow-up, even though the differences faded. Treatment was also related to a significant amelioration of biomarkers (platelet count, HDL, and D-dimer), whereas the 2 groups showed similar frequencies of adverse cardiac events. CONCLUSIONS: Addressing psychological well-being in the psychotherapeutic approach to ACS patients with depressive symptoms was found to entail important clinical benefits. It is argued that lifestyle changes geared toward cardiovascular health may be facilitated by a personalized approach that targets well-being.

Long-term injury after Takotsubo syndrome (stress cardiomyopathy).

Takotsubo syndrome is a clinical condition characterized by transient impairment of left ventricular contractility, in association with symptoms, increase in indices of myocardial necrosis, as well as electrocardiographic changes, but without a coronary culprit lesion, and often after a significant psychological or physical stress. Albeit very similar to acute coronary syndrome (ACS) as far as presentation and clinical course, Takotsubo syndrome was considered, up until recently, a condition with very favourable long-term prognosis, in view of the frequent complete functional recovery. More recently, several retrospective observational studies as well as registers, unexpectedly called attention to a significant incidence of major adverse cardiovascular events, not limited to the recovery period but also during the long-term follow-up, in a way very similar to the outcome of patients after ACS. Several negative prognostic factors have been isolated, such as physical stress as trigger of the condition, the presence of severe left ventricular dysfunction, and the consequent cardiogenic shock during the acute phase. These factors are able to classify better the patient's prognosis, both in the short- and long-term, and identify patients requiring a more stringent clinical follow-up, considering the higher likelihood of adverse cardiovascular events.

Preeclampsia in pregnancies complicated by systemic lupus erythematosus (SLE) nephritis: prophylactic treatment with multidisciplinary approach are important keys to prevent adverse obstetric outcomes.

INTRODUCTION: Systemic lupus erythematosus (SLE) commonly affects women of childbearing age. Hypertension, antiphospholipid syndrome, and lupus nephritis are risk factors for adverse maternal/fetal outcome. The aim of this retrospective cohort study is to compare pregnancy outcomes in patients with and without SLE nephritis, using a multidisciplinary approach and a broad prophylaxis protocol. MATERIALS AND METHODS: Data were collected from 86 pregnancies complicated by SLE. Twenty-seven women with nephropathy before pregnancy stated as the study group and 59 formed the control group. Each group received a prophylactic treatment based on their clinical characteristics. Results were expressed as mean ± SD, percentage and χ2-test (significant values when p < .05). RESULTS: The prophylactic treatment (60.4% of the patients) significantly controlled the complications related to some risk factors, such as antiphospholipid antibodies (aPL) and nephritis. Preeclampsia occurred in 14.8% of patients. Patients with pregestational hypertension showed a 2.75 odds ratio of adverse events when compared to the group without chronic hypertension. The presence of proteinuria was associated with a risk of preeclampsia 2.45 times greater, as well as serum creatinine >1.2 mg/dL, which was related to a risk 1.25 times higher than the risk observed in patients with serum creatinine <1.2 mg/dL. A 6-month inactive disease was associated with a better outcome. A value of Estimated Glomerular Filtration Rate (eGFR) < 90 mL/min/1.73 m2 resulted in a 18.73 times greater risk of preeclampsia, intrauterine growth restriction (IUGR), and preterm delivery. DISCUSSION: A multidisciplinary approach in a tertiary care center and a broad prophylactic treatment protocol to patients affected by SLE and complicated by nephritis may definitively foster a successful pregnancy.

Toward comprehensive measurement of protein hydration dynamics: Facilitation of NMR-based methods by reverse micelle encapsulation.

Protein-water interactions are a fundamental determinant of protein structure and function. Despite their importance, the molecular details of water orientations and dynamics near protein surfaces remain poorly understood, largely due to the difficulty of measuring local water mobility near the protein in a site-resolved fashion. Solution NMR-based measurement of water mobility via the nuclear Overhauser effect was presented as a method for performing comprehensive, site-resolved measurements of water dynamics many years ago. Though this approach yielded extensive insight on the dynamics and locations of waters buried within proteins, its promise for measuring surface hydration dynamics was impeded by various technical barriers. Over the past several years, however, this approach has been pursued anew with the aid of reverse micelle encapsulation of proteins of interest. The confined environment of the reverse micelle resolves many of these barriers and permits site-resolved measurement of relative water dynamics across much of the protein surface. Here, the development of this strategy for measuring hydration dynamics is reviewed with particular focus on the important remaining challenges to its widespread application.

Protein Polymer-Based Nanoparticles: Fabrication and Medical Applications.

Nanoparticles are particles that range in size from about 1⁻1000 nanometers in diameter, about one thousand times smaller than the average cell in a human body. Their small size, flexible fabrication, and high surface-area-to-volume ratio make them ideal systems for drug delivery. Nanoparticles can be made from a variety of materials including metals, polysaccharides, and proteins. Biological protein-based nanoparticles such as silk, keratin, collagen, elastin, corn zein, and soy protein-based nanoparticles are advantageous in having biodegradability, bioavailability, and relatively low cost. Many protein nanoparticles are easy to process and can be modified to achieve desired specifications such as size, morphology, and weight. Protein nanoparticles are used in a variety of settings and are replacing many materials that are not biocompatible and have a negative impact on the environment. Here we attempt to review the literature pertaining to protein-based nanoparticles with a focus on their application in drug delivery and biomedical fields. Additional detail on governing nanoparticle parameters, specific protein nanoparticle applications, and fabrication methods are also provided.

Electrocardiographic changes in patients with acute myocardial infarction caused by left main trunk occlusion.

BACKGROUND: Left main trunk (LMT) occlusion is a rare angiographic finding. The primary purpose was to investigate the ECG pattern of patients with angiographic confirmation of LMT as culprit lesion. METHODS: Forty-eight patients (32 men; mean age 73 years) with angiographic total (21 patients; 44%) or subtotal (27 patients; 56%) occlusion of the LMT were analyzed. Twenty patients (42%) were found to have concomitant coronary lesions. Eighteen patients (38%) required intra-aortic balloon pump support. RESULTS: A significant left axis deviation was observed in 26 cases (54%) and an intraventricular conduction delay in 32 patients (67%). The average QRS width and QTc interval were 122 and 433 ms, respectively. ST-segment elevation in lead aVR occurred in 32 patients (67%). ST-segment elevation in leads V2-5 and in leads I and aVL [classic left anterior descending (LAD) type] was frequently observed (18 cases; 35%). In six patients (13%), a partial LAD type was observed with ST-segment elevation in leads I and aVL, but not in peripheral leads. The remaining patients showed ST-segment elevation only in peripheral leads (12 cases), in inferior leads III + aVF (six cases), whereas six patients had no ST-segment elevation. Diffuse ST-segment depression only (>6 leads) was observed in 15 cases (31%). Eighteen patients (38%) died during hospitalization. CONCLUSION: ST-segment elevation in lead aVR or a LAD-type pattern can be associated with LMT disease. Other relevant aspects are the presence of cardiogenic shock at admission, the left axis deviation and marked prolongation of QTc interval and QRS width.

[Temporal evolution of antithrombotic therapy use in patients with acute coronary syndromes undergoing percutaneous coronary intervention in Italy: comparison between the EYESHOT and SCOPE registries]. / Analisi della recente evoluzione temporale dell'impiego della terapia antitrombotica nei pazienti con sindrome coronarica acuta sottoposti ad angioplastica coronarica in Italia: confronto dei registri EYESHOT e SCOPE.

BACKGROUND: Few data exist on temporal evolution of antithrombotic agent use in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) in Italy. We sought to compare data from the most recent prospective, multicenter, nationwide registries conducted in Italy, namely EYESHOT and SCOPE. METHODS: EYESHOT enrolled 2585 consecutive ACS patients, both ST-segment elevation myocardial infarction (STEMI) and non-ST elevation ACS (NSTE-ACS), admitted to 203 Italian coronary care units over a 3-week period (2-22 Dec 2013 and 27 Jan-16 Feb 2014). Among patients enrolled in EYESHOT, 1755 (67.9%) underwent PCI (52.6% with STEMI and 47.4% with NSTE-ACS). In the SCOPE registry, a total of 1363 patients undergoing PCI were enrolled over 3 months (15 Feb-15 Apr 2016) in 39 Italian cath lab centers at medium to high PCI volume: 331 (24.3%) with a diagnosis of STEMI and 1032 (75.7%) with a diagnosis of NSTE-ACS. RESULTS: Over 2 years, the use of clopidogrel in the cath lab significantly decreased (from 11% to 8% in STEMI; p=0.06 and from 9% to 5% in NSTE-ACS; p=0.0002), while the administration of ticagrelor dramatically increased (from 14% to 37%; p<0.0001 in STEMI and from 7% to 44%; p<0.0001 in NSTE-ACS). At discharge, a significant decrease in the use of clopidogrel (from 32% to 21% in STEMI; p=0.02, and from 47% to 24% in NSTE-ACS; p<0.0001) and a concomitant increase in the novel P2Y12 receptor inhibitor prescription occurred, particularly among NSTE-ACS patients (from 8% to 14% for prasugrel; p=0.002 and from 43% to 58% for ticagrelor; p=0.03). CONCLUSIONS: From the present analysis on ACS patients undergoing PCI enrolled in EYESHOT and SCOPE registries, a significant increase in the use of novel P2Y12 receptor inhibitors was observed, both at the time of PCI and at discharge.

[Dystrophic Calcinosis Cutis: a rare fearsome issue of Chronic Kidney Disease].

Disorders of calcium-phosphate-parathormone balance, are very important issues in ESRD patients, that may lead to severe complications, as dystrophic calcinosis cutis, a rare disease, caused by calcium salt deposits in cutaneous or subcutaneous tissues and many organs. We present the case of a 47 years old woman, in ESRD due to membranous glomerulopathy, treated by peritoneal dialysis, who, after 7 months of dialysis, developed painful masses on second finger and fifth metacarpus of the right hand. Laboratory and instrumental data showed hyperparathyroidism with a parathyroid mass consistent with adenoma. Increasing of therapy with phosphate binders and cinacalcet only, was not effective to solve cutaneous masses, that were biopsied. Histological exam revealed deposition of amorphic material with calcific component, consistent with cutaneous dystrophic calcinosis. We further increased dialysis and therapy and we observed complete regression of masses in 2 months.

Balloon aortic valvuloplasty as a bridge-to-decision in high risk patients with aortic stenosis: a new paradigm for the heart team decision making.

BACKGROUND: Whilst the majority of the patients with severe aortic stenosis can be directly addressed to surgical aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI), in some instances additional information may be needed to complete the diagnostic workout. We evaluated the role of balloon aortic valvuloplasty (BAV) as a bridge-to-decision (BTD) in selected high-risk patients. METHODS: Between 2007 and 2012, the heart team in our Institution required BTD BAV in 202 patients. Very low left ventricular ejection fraction, mitral regurgitation grade ≥ 3, frailty, hemodynamic instability, serious comorbidity, or a combination of these factors were the main drivers for this strategy. We evaluated how BAV influenced the final treatment strategy in the whole patient group and in each specific subgroup. RESULTS: Mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) was 23.5% ± 15.3%, age 81 ± 7 years. In-hospital mortality was 4.5%, cerebrovascular accident 1% and overall vascular complications 4% (0.5% major; 3.5% minor). Of the 193 patients with BTD BAV who survived and received a second heart team evaluation, 72.6% were finally deemed eligible for definitive treatment (25.4% for AVR; 47.2% for TAVI): 96.7% of patients with left ventricular ejection fraction recovery; 70.5% of patients with mitral regurgitation reduction; 75.7% of patients who underwent BAV in clinical hemodynamic instability; 69.2% of frail patients and 68% of patients who presented serious comorbidities. CONCLUSIONS: Balloon aortic valvuloplasty can be considered as bridge-to-decision in high-risk patients with severe aortic stenosis who cannot be immediate candidates for definitive transcatheter or surgical treatment.

Risk of Stroke in Patients with Stable Coronary Artery Disease Undergoing Percutaneous Coronary Intervention versus Optimal Medical Therapy: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Stroke is a rare but serious adverse event associated with percutaneous coronary intervention (PCI). However, the relative risk of stroke between stable patients undergoing a direct PCI strategy and those undergoing an initial optimal medical therapy (OMT) strategy has not been established yet. This study sought to investigate if, in patients with stable coronary artery disease (SCAD), an initial strategy PCI is associated with a higher risk of stroke than a strategy based on OMT alone. METHODS: We performed a meta-analysis of 6 contemporary randomized control trials in which 5673 patients with SCAD were randomized to initial PCI or OMT. Only trials with stent utilization more than 50% were included. Study endpoint was the rate of stroke during follow up. RESULTS: Mean age of patients ranged from 60 to 65 years and stent utilization ranged from 72% to 100%. Rate of stroke was 2.0% at a weighted mean follow up of 55.3 months. On pooled analysis, the risk of stroke was similar between patients undergoing a PCI plus OMT and those receiving only OMT (2.2% vs. 1.8%, OR on fixed effect = 1.24 95%CI: 0.85-1.79). There was no heterogeneity among the studies (I2 = 0.0%, P = 0.15). On sensitivity analysis after removing each individual study the pooled effect estimate remains unchanged. CONCLUSIONS: In patients with SCAD an initial strategy based on a direct PCI is not associated with an increased risk of stroke during long-term follow up compared to an initial strategy based on OMT alone.

Conservative management of chronic kidney disease stage 5: role of angiotensin converting enzyme inhibitors.

BACKGROUND: Benefits and risks of angiotensin converting enzyme inhibitors (ACE-I) in advanced chronic kidney disease (CKD) are controversial. We tested the role of ACE-I in slowing the progression of renal damage in a real-world elderly population with CKD stage 5. METHODS: We evaluated all patients consecutively referred to our CKD stage 5 outpatient clinic from January 2002 to December 2013. Chronicity was defined as two consecutive estimated glomerular filtration rate (eGFR) measurements below 15 ml/min/1.73 m2. We retrieved parameters of interest at baseline and assessed eGFR reduction rate during follow-up. We estimated GFR by the 4-variable Modification of Diet in Renal Disease (MDRD) formula. RESULTS: Mean age of the 342 subjects analyzed was 72 years and eGFR 10 ml/min/1.73 m2. In the 188 patients on ACE-I at baseline, the subsequent annual rate of eGFR reduction was less than a third of that found in the 154 patients off ACE-I. Across phosphate quartiles, baseline eGFR significantly decreased while its annual reduction rate significantly increased. Of the original cohort, 60 patients (17 %) died, 201 (59 %) started dialysis and 81 (24 %) were still in conservative treatment at the end of the study. Multivariate analysis identified age, phosphate, proteinuria, baseline eGFR and its rate of progression as independent risk factors directly or inversely predictive of progression to dialysis. ACE-I use significantly reduced by 31 % the risk of dialysis. CONCLUSIONS: Our study shows that proteinuria independently predicts further renal damage progression even in end-stage renal disease patients not yet in dialysis. In our cohort of elderly patients with very advanced CKD, ACE-I was effective in slowing down further renal damage progression.

Biolimus-a9 eluting stent implantion for unprotected left main coronary artery stenosis: 9-month strut coverage as assessed by optical coherence tomography.

OBJECTIVE: To evaluate strut coverage after biolimus-A9 eluting stent (BES) implantation for unprotected left main artery (ULMA) stenosis during follow-up and identify features associated with the length of uncovered stent segment, as assessed by frequency domain-optical coherence tomography (FD-OCT). BACKGROUND: Incomplete stent strut coverage is a risk factor for late stent thrombosis. Long-term interaction between vessel wall and BES in the context of ULMA stenting has not been investigated in depth. METHODS: We prospectively enrolled 32 patients with ULMA stenosis treated with BES. FD-OCT was performed at 9-month follow-up. Both malapposed and uncovered segment length were indexed for the segment between the distal and proximal cross-sections in which stent struts were circumferentially visible. Patients were divided into two groups according to the median value of maximal indexed uncovered segment length. Study endpoints were the rate of strut coverage and predictors of high uncovered segment length. RESULTS: We analyzed 3622 struts. The rate of covered struts was 87%. A high correlation was found between malapposed and uncovered segment length (r = 0.82; P<.001). The median value of indexed-uncovered segment length was 0.308. On multivariable analysis, patients undergoing final kissing balloon were at lower risk of high uncovered segment length (odds ratio, 0.81; 95% confidence interval, 0.008-0.837; P=.04). CONCLUSION: In patients undergoing BES implantation for treatment of ULMA stenosis, the rate of 9-month strut coverage is high. The use of final kissing balloon reduces the risk of high uncovered stent segment length.

Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention.

Several prospective studies have shown that high on-clopidogrel platelet reactivity (HPR) in patients undergoing percutaneous coronary intervention (PCI) is a risk factor for ischemic events. All studies were insufficiently powered to detect differences in stroke between patients with HPR and those without. Therefore, we performed a systematic review and meta-analysis of available publications aimed at determining whether patients undergoing PCI with HPR are also at increased risk of stroke. We searched for prospective studies enrolling patients undergoing PCI and treated with aspirin and clopidogrel that reported on clinical relevance of HPR to adenosine diphosphate. Study end point was the rate of stroke. We also investigated whether there was an interaction on the relative risk of stroke between HPR, clinical presentation, duration of follow-up, or laboratory methods. Fourteen studies including 11,959 patients were deemed eligible. On pooled analysis, the risk of stroke was higher in patients with HPR compared with patients with no HPR (1.2% vs 0.7%, relative risk on fixed effect 1.84, 95% confidence interval 1.21 to 2.80). There was no heterogeneity among the studies (I(2) = 0%, p = 0.5). Clinical presentation (p = 0.39 for interaction), duration of follow-up (p = 0.87 for interaction), and laboratory method for detection of HPR (p = 0.99 for interaction) did not affect the relative increase in the risk of stroke in patients with HPR compared with patients with no HPR. In conclusion, in patients with coronary artery disease undergoing PCI, the presence of HPR to adenosine diphosphate is a risk factor for stroke.

Diagnostic performance of standard electrocardiogram for prediction of infarct related artery and site of coronary occlusion in unselected STEMI patients undergoing primary percutaneous coronary intervention.

AIMS: To evaluate the relationship between ECG patterns and infarct related artery (IRA) in an all-comer population with ST-segment elevation myocardial infarction (STEMI) and validate current criteria for identifying IRA (right coronary artery (RCA) versus left circumflex artery (LCA)) in inferior STEMI and for diagnosing left main (LM) or left anterior descendent artery occlusion (LAD) in anterior STEMI. METHODS AND RESULTS: We retrospectively analysed ECGs at presentation and coronary angiogram in 885 consecutive patients undergoing primary percutaneous coronary intervention. Six ECG patterns were identified: anterior-STEMI (n=433; 49.0%), inferior-STEMI (i=365; 43.0%), lateral-STEMI (n=43; 5.0%), left bundle branch block (n=26; 3.0%), posterior-STEMI (n=7; 1.0%) and de Winter sign (n=7; 1.0%). The last two ECG patterns were univocally associated with LCA and proximal LAD occlusion respectively. In patients with inferior STEMI, predefined ECG algorithms showed high sensitivity(>90%) for RCA occlusion and high specificity(>90%) for LCA. The diagnostic performance was mainly determined by RCA dominance. In anterior STEMI the vectorial analysis of ST deviation in both frontal and horizontal planes could identify patients with LM/proximal LAD occlusion (adjusted-odds ratio for in-hospital mortality =2.45, 95% confidence interval: 1.31-4.56, p = 0.005) with low sensitivity (maximum 60%; using ST-depression in lead II, III, aVF + ΣSTE aVR + V1-ST depression V6≥0) and high specificity (maximum 95%; using ST-depression in inferior leads + ST-depression in V6). CONCLUSION: In STEMI undergoing primary percutaneous coronary intervention, six ECG patterns can be identified with a non-univocal relationship to the IRA. In inferior STEMI, vectorial analysis of ST deviation identifies IRA with a high appropriateness only when RCA is the dominant artery. In anterior STEMI, criteria derived from both frontal and horizontal planes identify LM/proximal LAD occlusion with high specificity but low sensitivity.

Impact of a territorial ST-segment elevation myocardial infarction network on prognosis of patients with out-of-hospital cardiac arrest.

INTRODUCTION: We sought to assess the effect of a territorial system of care for ST-elevation myocardial infarction (STEMI) on the outcome of out-of-hospital cardiac arrest (OOHCA). MATERIALS AND METHODS: We enrolled 720 patients who experienced a witnessed OOHCA of presumed cardiac origin during a four-year period in an area with a STEMI network and for whom resuscitation was attempted. RESULTS: Overall, 242 (33.6%) patients had return of spontaneous circulation (ROSC), 645 (90%) died before discharge. We observed a trend toward decreased overall mortality for OOHCA between the years 2004 and 2007, both in the entire population and in patients with ROSC (2004=94%; 2005=89%; 2006=85%; 2007=89%; P=0.064; 2004=81%; 2005=69%; 2006=65%; 2007=60%; P=0.076, respectively). On multivariable analysis, age, crew-witnessed arrest and presence of shockable rhythm were independent predictors of mortality. Patients who experienced OOHCA in the year 2006 (OR=0.47; 95% CI: 0.21-1.05; P=0.07) and 2007 (OR=0.51; 95% CI: 0.23-1.12; P=0.09) showed a strong trend toward decreased risk of mortality compared to year 2004. In patients with ROSC, the year 2007 was associated with a significant lower risk of mortality compared to year 2004 (OR=0.38; 95% CI: 0.15-0.96; P=0.04). CONCLUSIONS: Implementation of a territorial network of care for STEMI appears to be associated with reduced mortality OOHCA patients.