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Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome-MetS, and type 2 diabetes mellitus-DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and real-time quantitative polymerase chain reaction (RT-qPCR) analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by screening of 30 secreted cytokines, with a significant reduction in vascular endothelial growth factor (VEGF) and endoglin confirmed by enzyme-linked immunoassay (ELISA). DM2-CSCs showed significantly reduced support for endothelial cells in angiogenic assays, and significantly increased Hsub2/subOsub2/subrelease and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. © 2022 The Authors. The Journal of Pathology published by John Wileyamp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

There is clear association between the intensity of the acute inflammatory response during acute myocardial infarction (AMI) and adverse prognosis after AMI. Interleukin‐1 (IL‐1) is a pro‐inflammatory cytokine released during AMI and involved in adverse remodeling and heart failure (HF). We describe a study to evaluate the safety and efficacy of IL‐1 blockade using an IL‐1 receptor antagonist (anakinra) during the acute phase of ST‐segment elevation myocardial infarction (STEMI). The Virginia Commonwealth University–Anakinra Remodeling Trial‐3 (VCU‐ART3; http://www.ClinicalTrials.gov NCT01950299) is a phase 2, multicenter, double‐blinded, randomized, placebo‐controlled clinical trial comparing anakinra 100 mg once or twice daily vs matching placebo (1:1:1) for 14 days in 99 patients with STEMI. Patients who present to the hospital with STEMI within 12 hours of symptom onset will be eligible for enrollment. Patients will be excluded for a history of HF (functional class III–IV), severe valvular disease, severe kidney disease (stage 4–5), active infection, recent use of immunosuppressive drugs, active malignancy, or chronic autoimmune/auto‐inflammatory diseases. We will measure the difference in the area under the curve for C‐reactive protein between admission and day 14, separately comparing each of the anakinra groups with the placebo group. The P value will be considered significant if

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence-based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 randomized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1 blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpoints will be placebo-corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.

Background This meta-analysis aims to assess the impact of a voltage-guided substrate modification by targeting low-voltage area (LVA) in addition to pulmonary vein isolation (PVI) in patients undergoing catheter ablation for atrial fibrillation (AF). Methods MEDLINE/PubMed, Cochrane Library, and references reporting AF ablation and “voltage* OR substrate* OR fibrosis OR fibrotic area*” were screened and studies included if matching inclusion and exclusion criteria. Results Six studies were included. Patients enrolled were 885 (517 in the study group and 368 in the control group). Median age was 60 years; 92% had nonparoxysmal AF. At a mean follow-up of 17 months, 70% of patients in the study group vs. 43% in the control group were free from AF/atrial tachycardia (AT) recurrences (odds ratio [OR] = 3.41, 95% confidence interval [CI] 2.22–5.24). LVA ablation in addition to PVI was more effective than PVI alone and PVI + conventional wide empirical ablation (70% vs. 43%, OR = 3.41, 95% CI 2.22–5.24), without increasing the adverse event rate (2.5% vs. 6%, OR = 0.43, 95% CI 0.15–1.26). Compared to PVI + conventional wide empirical ablation, LVA ablation reduced the occurrence of postablation AT (14% vs. 46%, OR = 0.16, 95% CI 0.07–0.37), procedure time (176 min vs. 220 min, OR = 0.36, 95% CI 0.24–0.56), fluoroscopy time (25 min vs. 31 min, OR = 0.22, 95% CI 0.12–0.39), and radiofrequency time (55 min vs. 90 min, OR = 0.49, 95% CI 0.27–0.90). Conclusions A voltage-guided substrate modification by targeting LVA in addition to PVI is more effective, safer, and holds a lower proarrhythmic potential than conventional ablation approaches. Further randomized studies are necessary to confirm these findings.

AIM To determine the potential clinical impact of OCT (Optical Coherence Tomography) during primary percutaneous coronary intervention in patients presenting with ACS (Acute Coronary Syndrome). METHODS AND RESULTS FORMIDABLE is a multicentre retrospective registry enrolling all patients presenting with ACS and treated with an OCT-guided approach, while the USZ registry enrolled patients treated with a standard angiography guided approach. Multivariate adjustment was performed via a propensity score matching. The number stents useds was the primary outcome, while the incidence of MACE (a composite of death, myocardial infarction, target vessel revascularization, and stent thrombosis) was the secondary endpoint. A total of 285 patients OCT-guided and 1,547 angiography guided patients were enrolled, resulting in 270 for each cohort after propensity score with matching. Two stents were used in 12% versus 34%; 3 stents in 8% versus 38% of the patients (P

Background: The risk/benefit balance of transcatheter aortic valve implantation (TAVI) in patients with low-gradient aortic stenosis (LGAS) remains to be well defined. Aim of the study was to investigate the impact of LGAS in patients undergoing TAVI. Methods: Medline, Cochrane Library, and Scopus were searched for articles reporting outcome of patients with LGAS undergoing TAVI. The primary endpoint was 12-months all-cause mortality and the secondary endpoint was 30-day all-cause mortality. Using event-rates as dependent variable, a meta-regression was performed to test for interaction between baseline clinical features (age, gender, diabetes mellitus, coronary artery disease, left ventricular ejection fraction (LVEF) and type of implanted valve) and transaortic gradient for the primary endpoint. Results: Eight studies with a total of 12,589 patients were included. Almost one-third of the patients presented with LGAS (27.3%: 24.4–29.2). Median LVEF was 48% in patients with LGAS and 56% in patients with high-gradient AS. Patients with LGAS were more likely to have diabetes mellitus, previous coronary artery disease, higher mean Logistic EuroSCORE, and lower EF. At 12 (12–16.6) months, low transaortic gradient emerged as independently associated with all-cause death, both if evaluated as a dichotomous and continuous value (respectively OR 1.17; 1.11–1.23 and OR 1.02; 1–1.04, all CI 95%). Clinical variables, including EF did not affect this result. Conclusions: In a population of TAVI patients, LGAS appears to be independently related to dismal prognosis. © 2016 Wiley Periodicals, Inc.

Basic and translational research on lung biology has discovered multiple progenitor cell types, specialized or facultative, responsible for turnover, renewal, and repair. Isolation of populations of resident lung progenitor cells (LPCs) has been described by multiple protocols, and some have been successfully applied to healthy human lung tissue. We aimed at understanding how different cell culture conditions may affect, in vitro, the phenotype of LPCs to create an ideal niche-like microenvironment. The influence of different substrates (i.e., fibronectin, gelatin, laminin) and the impact of a three-dimensional/two-dimensional (3D/2D) culture switch on the biology of LPCs isolated as lung spheroids (LSs) from normal adult human lung biopsy specimens were investigated. We applied a spheroid culture system as the selective/inductive step for progenitor cell culture, as described in many biological systems. The data showed a niche-like proepithelial microenvironment inside the LS, highly sensitive to the 3D culture system and significantly affecting the phenotype of adult LPCs more than culture substrate. LSs favor epithelial phenotypes and LPC maintenance and contain cells more responsive to specific commitment stimuli than 2D monolayer cultures, while secreting a distinctive set of paracrine factors. We have shown for the first time, to our knowledge, how culture as 3D LSs can affect LPC epithelial phenotype and produce strong paracrine signals with a distinctive secretomic profile compared with 2D monolayer conditions. These findings suggest novel approaches to maintain ex vivo LPCs for basic and translational studies.

Transcatheter aortic valve replacement (TAVR), also known as transcatheter aortic valve implantation (TAVI), is being used with increasing frequency in patients with severe aortic stenosis at high or prohibitive surgical risk. A number of devices are becoming available for TAVR, and competence in using them is mandatory to maximize the safety and efficacy of TAVR, while individualizing device selection in keeping with patient features. The ACURATE TF is a novel promising device for transfemoral TAVR. However, its peculiar features may require additional maneuvers in case of complications. We hereby report the case of a patient undergoing transfemoral TAVR with the ACURATE TF device, in whom lowermost deployment was complicated by massive aortic regurgitation. With two separate remedial actions, the balloon pull and lasso techniques, we were able to pull back the device and significantly reduce post-TAVR aortic regurgitation. Awareness of this complication and the possible use of these two techniques may increase the safety and efficacy of TAVR with this and other new devices. © 2015 Wiley Periodicals, Inc.

The role of transcatheter mitral valve repair with MitraClip implantation is becoming increasingly important for high-risk surgical patients with significant mitral regurgitation. Eligibility criteria for MitraClip are however rather strict, and the risk-benefit balance of this device in off-label settings remains unclear. Patients with prior heart transplantation may represent particularly challenging candidates for MitraClip, given their peculiar atrial anatomy. We hereby present the case of a 72-year-old gentleman with prior heart transplantation and significant mitral regurgitation who, after heart team consensus, was referred to us for MitraClip implantation. After careful planning, we were able to successfully implant two clips, achieving a significant improvement in the severity of the mitral regurgitation. Similarly favorable findings were confirmed at 3-month clinical and transthoracic/transesophageal echocardiographic follow-up. This clinical vignette highlights the key procedural milestones for successfully implanting MitraClip in patients with significant mitral regurgitation and prior heart transplantation. © 2015 Wiley Periodicals, Inc.

Introduction The increasing use of primary percutaneous coronary intervention (pPCI) has improved clinical outcome in ST-segment elevation myocardial infarction (STEMI) patients, but the impact of sex on early and mid-term outcomes remains to be defined. Methods Medline, Cochrane Library, Biomed Central, and Google Scholar were searched for articles describing differences in baseline, periprocedural, and midterm outcomes after pPCI, by sex. The primary end point was all-cause mortality at early and mid-term follow-up. Secondary endpoints included in-hospital bleeding and stroke. Results Sixteen studies were included. Women were older, had more frequent hypertension, diabetes mellitus, and hypercholesterolemia, as well as longer ischemia time and more shock at presentation. Men were more likely to have had a previous myocardial infarction. Female sex emerged as independently associated to early mortality (OR 1.1; 95%CI, 1.02–1.18) but not to mid-term mortality (OR, 1.01; 95%CI, 0.99–1.03). The pooled analysis showed a significantly higher risk of in hospital stroke (OR, 1.69; 95%CI, 1.11–2.56) and major bleeding (OR, 2.04; 95%CI, 1.51–2.77) in women. Conclusions As compared to men, women undergoing pPCI have more bleedings and strokes, and a worse early, but not mid-term mortality. These findings may allow a better risk stratification of pPCI patients.

Introduction Transcatheter aortic valve implantation (TAVI) may be performed using the transfemoral (TF) or transapical (TA) approach in most patients with aortic stenosis. The impact of access choice on peri-procedural and midterm results remains to be defined. Methods Medline and Cochrane Library were searched for articles describing differences in baseline, peri-procedural, and midterm outcomes among patients undergoing TF or TA TAVI. The primary end-point was all-cause mortality after at least 1-year follow-up, while secondary end-points were 30 days mortality and in-hospital complications (bleeding and cerebrovascular events). The independent impact of access choice was evaluated with pooled analysis using a random-effect model. Results Thirteen studies with 10,468 patients were included. TF was the most exploited strategy (69.5% vs. 30.5%). After adjusting for confounding variables, 30-day and midterm follow-up mortality (median 365 days, range 222–400) were lower in TF patients with a pooled adjusted odds ratio of 0.81 (0.68–0.97 I2 99%) and 0.85 (0.80–0.90 I2 96%), respectively. Regarding periprocedural outcomes, TF reduced risk of bleedings and strokes (OR of 0.74 [0.66–0.82 I2 95%] and 0.91 [0.83–0.99] I2 86%, respectively). Conclusions The TF approach reduces mortality in TAVI patients, due to lower rates of periprocedural bleedings and strokes. (J Interven Cardiol 2014;27:500–508)

Introduction Different definitions of periprocedural myocardial infarction (MI) after percutaneous coronary intervention (PCI) have been provided, but their impact on prognosis remains to be determined. Methods Procedural data from consecutive patients undergoing PCI from 2009 to 2011 were revised to adjudicate diagnosis of periprocedural MI according to CK-MB increase (>3 × URL and >5 × URL), to troponin increase (>3 × 99th percentile URL and >5 × 99th percentile URL) and to recent 2012 Task Force and Society for Cardiovascular Angiography and Interventions (SCAI) definitions. Major adverse cardiovascular events (MACE) was the primary end-point. Results Seven hundred twelve patients were enrolled; after 771 days, 115 (16.7%) patients experienced MACE. One hundred ninety patients were diagnosed with a periprocedural MI defined as elevation of troponin >5 × 99th percentile of URL. When adjudicating 2012 Task Force definition on these patients, 46 were excluded and 1.4% of them experienced a MACE and 0.3% died, while among 144 with periprocedural MI, 2.9% reported a MACE and 1.3% died. After appraisal of SCAI definition, 176 patients were excluded, 3.8% of them with a MACE and 1.4% died, and for those with periprocedural MI, 0.5% experienced a MACE and 0.1% died. Similar low performance was appraised after reclassification of patients from more than 3 of upper limit of CK-MB and of troponin. At multivariate analysis, none of these definitions related to adverse events. Conclusion Periprocedural MI represents a frequent complication for patients undergoing PCI. All present definitions share a still not satisfactory discrimination between patients with and without adverse events at follow-up, stressing the need for more accurate definitions. (J Interven Cardiol 2014;27:482–490)

Introduction: Duration of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) hospitalization remains to be defined, both for patients treated medically and for those undergoing percutaneous transluminal coronary angioplasty (PTCA). Methods: PubMed, Cochrane, and Google Scholar were systematically searched for studies including patients presenting with ACS, and treated either with DAPT longer than or shorter than 12 months. Multivariable‐adjusted risk estimates for death and recurrent ACS with stopping DAPTafter 12 months (odds ratios [OR] 95% confidence intervals [CI]) were pooled after logarithmic transformation according to random‐effect models with inverse‐ variance weighting. Results: Five studies with 49,586 patients were included. Median age was 66 (64–67) years, with 67% (65–75) males. Myocardial infarction (MI) represented the admission diagnosis for 88% (60–100) of the patients, and 66% (50–74) were treated with stenting. After a follow‐up of 2.1 years (1.5–2.7), 40% (35–46) still on DAPT after 12 months and the rates of death or recurrent ACS were 16.6 (14.5–17.0). Risk of adverse events for patients stopping DAPTafter 1 year was significantly increased (OR ¼1.19 [1.07–1.32]) for those receiving stents, but not for patients managed medically (OR ¼1.13 [0.95–1.35]). The increased risk did not vary according to age, gender, myocardial infarction as admission diagnosis, and kind of stent. Conclusions:InterruptionofDAPTover12monthsafterACSincreasestheriskofadverseeventsforpatientstreated with PTCA, but not for those managed conservatively, independently from baseline features and admission diagnosis. This hypothesis‐generating finding should be tested in randomized controlled trials. (J Interven Cardiol 2014;9999:1–9)

Drug-coated balloons are a new tool for the treatment of patients with coronary artery disease. The main feature of this technology is a rapid and homogenous transfer of an antiproliferative drug (paclitaxel) to the vessel wall just at the time of balloon inflation, when neointimal proliferation, in response to angioplasty, is the highest. Moreover, drug-coated balloons share adjuntive advantages over stents: the absence of permanent scaffold and polymer, the respect of the original coronary anatomy, and limited inflammatory stimuli, thereby allowing for short-term dual antiplatelet therapy. To this day, a lot of devices are available in the market, with limited scientific data for the vast majority of them. Thus, the Italian scientific society of interventional cardiologists GISE decided to coordinate the efforts of a group of reknown experts on the field, in order to obtain a Position Paper on the correct use of drug-coated balloons in all the settings of coronary artery disease, giving a class of indication to each one, based on the clinical evidence. This Position Paper represents a quick reference for operators, investigators, and manufactures to promote the understanding and the correct use of the drug-coated balloon technology in everyday clinical practice. © 2013 Wiley Periodicals, Inc.

Aims: Randomized clinical trials (RCTs) are the most reliable evidence, even if they require important resource and logistic efforts. Large, cost-free and real-world datasets may be easily accessed yielding to observational studies, but such analyses often lead to problematic results in the absence of careful methods, especially from a statistic point of view. We aimed to appraise the performance of current multivariable approaches in the estimation of causal treatment and effects in studies focusing on drug-eluting stents (DES). Methods and Results: Pertinent studies published in the literature were searched, selected, abstracted, and appraised for quality and validity features. Six studies with a logistic regression were included, all of them reporting more than 10 events for covariates and different length of follow-up, with an overall low risk of bias. Most of the 15 studies with a Cox proportional hazard analysis had a different follow-up, with less than 10 events for covariates, yielding an overall low or moderate risk of bias. Sixteen studies with propensity score were included: the most frequent method for variable selection was logistic regression, with underlying differences in follow-up and less than 10 events for covariate in most of them. Most frequently, calibration appraisal was not reported in the studies, on the contrary of discrimination appraisal, which was more frequently performed. In seventeen studies with propensity and matching, the latter was most commonly performed with a nearest neighbor-matching algorithm yet without appraisal in most of the studies of calibration or discrimination. Balance was evaluated in 46% of the studies, being obtained for all variables in 48% of them. Conclusions: Better exploitation and methodological appraisal of multivariable analysis is needed to improve the clinical and research impact and reliability of nonrandomized studies. (J Interven Cardiol 2012;25:611–621)

Background: Twelve-month dual antiplatelet therapy (DAT) with aspirin and clopidogrel after drug-eluting stent (DES) implantation is routinely recommended. It is unclear if prolonged (>12-month) DAT is also favorable. We compared the outcome of patients discontinuing DAT 12 months after off-label DES implantation versus those with DAT for >12 months. Methods: Baseline, treatment, and outcome data of patients undergoing off-label DES implantation and free from events 11.5 months after index procedure were retrospectively retrieved. Those discontinuing DAT between 11.5 and 12.5 months (12-month DAT group) were compared to those discontinuing DAT after 12.5 months (>12-month DAT group). The primary end-point was the long-term (>24-month) rate of major adverse cerebro-cardiovascular events (MACCE). Results: Two hundred seventy-two patients met study inclusion criteria: 133 (48.9%) in the 12-month DAT group and 139 (51.1%) in the >12-month DAT group (who were on DAT for an average of 24 months). After an average of 36 months after DES implantation, 14 patients (5.1%) developed MACCE, with 6 (3.5%) cardiac deaths, 7 (2.2%) myocardial infarctions, no stroke, and 5 (1.8%) repeat revascularizations. The >12-month DAT group had a significantly lower risk of MACCE (1 [0.7%] vs. 13 [9.8%] in the 12-month DAT group, P < 0.001) and myocardial infarction (0 vs. 7 [5.3%], P = 0.006), with such differences confirmed at multivariable propensity-adjusted analyses. No significant differences in terms of minor or major bleedings occurred. Conclusions: In this retrospective registry, patients with off-label DES implantation receiving prolonged (>12 months) DAT presented with lower rates of MACCE and myocardial infarction. (J Interven Cardiol 2012;25:596–603)

Background Percutaneous dilatational tracheostomy (PDT) is a common procedure in intensive care units and the identification of the best technique is very important. We performed a systematic review and meta-analysis of randomized studies comparing different PDT techniques in critically ill adult patients to investigate if one technique is superior to the others with regard to major and minor intraprocedural complications. Methods BioMedCentral and other database of clinical trials were searched for pertinent studies. Inclusion criterion was random allocation to at least two PDT techniques. Exclusion criteria were duplicate publications, nonadult studies, and absence of outcome data. Study Design Population, clinical setting, and complications were extracted. Results Data from 1130 patients in 13 randomized trials were analyzed. Multiple dilators, single-step dilatation, guide wire dilating forceps, rotational dilation, retrograde tracheostomy, and balloon dilation techniques were always performed in the intensive care unit. The different techniques and devices appeared largely equivalent, with the exception of retrograde tracheostomy, which was associated with more severe complications and more frequent need of conversion to other techniques when compared with guide wire dilating forceps and single-step dilatation techniques. Single-step dilatation technique was associated with fewer failures than rotational dilation, and fewer mild complications in comparison with balloon dilation and guide wire dilating forceps (all P

Objectives: To evaluate the early and long-term outcomes of patients with normal left ventricular function who undergo elective unprotected left main coronary artery (ULMCA) percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Background: Although the standard of care for patients with ULMCA disease is coronary artery bypass surgery, the current guidelines recommend PCI in clinical conditions that predict an increased risk of adverse surgical outcomes. The long-term outcomes of patients with low risk of adverse surgical outcomes who undergo PCI are unknown. Methods: Data from a multicenter international registry, which included 221 consecutive patients from four institutions with normal left ventricular function who underwent elective ULMCA PCI with DES from 2002 to 2009, were collected. Results: There was no cardiac death, Q-wave myocardial infarction, target lesion revascularization (TLR), stent thrombosis, or stroke within the first 30 days. Seven (3%) patients had periprocedural myocardial infarction. Follow-up angiography was performed in 136 (62%) patients. Kaplan–Meier event-free survival curves at 1 year for cardiac death and TLR rates were 97.7% ± 1.0% and 92.9% ± 1.8%, respectively. At the mean follow-up of 44.8 ± 22.8 months, the event-free rates for cardiac death and TLR were 95.5% ± 1.5% and 88.9% ± 2.3%, respectively. Multivariate analyses identified the predictors of cardiac death: age ≥ 75 years (P = 0.015) and history of myocardial infarction (P = 0.017). Conclusions: Elective ULMCA PCI with DES in patients with normal left ventricular function is safe and effective with excellent short-term outcomes and favorable long-term outcomes and may be a viable option for low-risk patients with normal left ventricular function. © 2010 Wiley-Liss, Inc.

There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet-based process with a final meeting on 28 June 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic β-blockade, early aspirin therapy, the use of pre-operative intra-aortic balloon counterpulsation, and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic β-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

Background While the role of hemoglobin in heart failure and renal disease has been investigated, little is known about its effect on clinical exercise test performance and mortality in patients referred for routine exercise treadmill testing (ETT). Hypothesis Patients with low hemoglobin will have poor exercise capacity and would be at increased risk of mortality and cardiovascular (CV) events. Methods Clinical variables, laboratory values, and exercise treadmill data were obtained for 1,799 patients referred for routine ETT from 1997 to 2004. All-cause mortality was obtained from the United States Social Security death index and autopsy reports or clinical notes were used to determine CV events and mortality. P values < 0.05 were considered significant. Results Our population had a mean age of 58 ± 12 years, 16% had diabetes, 53% had hypertension, 35% had hypercholesterolemia, and 67% had a history of smoking. During follow-up, 10.3% of patients died, 3.9% of patients died of CV causes, and 11.6% had cardiovascular events. Anemic patients (hemoglobin [Hgb] < 13 g/dL) achieved lower metabolic equivalents (METs) than nonanemic patients and had more ST-segment depression (15.5% versus 8.6%, p < 0.004). Proportional hazard analysis demonstrated that hemoglobin was significantly associated with all-cause mortality (p < 0.0007), CV mortality (p < 0.009), and CV events (p < 0.01). Kaplan-Meier survival analysis demonstrated that anemic patients had significantly higher mortality and CV events. Conclusion Hemoglobin is significantly associated with exercise performance, ST-segment depression during ETT, mortality, and cardiovascular events. The incorporation of hemoglobin may add diagnostic and prognostic information to ETT. Copyright © 2009 Wiley Periodicals, Inc.

Coronary angiography, despite its inherent invasiveness and need for contrast media and radiographic exposure, is still routinely employed every year for the diagnostic and therapeutic management of millions of patients with or at risk for coronary artery disease. Whereas approximate visual estimation is the most common way to evaluate coronary angiography findings, since the late 1980s a number of investigators have developed and investigated methods of quantitative coronary angiography (QCA) analysis exploiting automated or semi-automated edge detection. Despite the inherent drawback of QCA due to its focus on the contrast-filled lumen of the vessel, QCA has offered and continues to offer important insights for clinical research and, in selected cases, clinical practice. This review aims thus to provide a comprehensive and updated viewpoint on the actual role of QCA.

Coronary bifurcation lesions represent an area of ongoing challenge in interventional cardiology. Contemporary studies using drug-eluting stents report a reduction in main vessel (MV) restenosis; however, residual stenosis and restenosis at side-branch ostium remain an issue. Multiple two-stent bifurcation strategies exist, including T-stenting, V-stenting, simultaneous kissing stenting, culotte stenting, and crush stenting technique. Each strategy has its own advantages and disadvantages, but on the basis of results of numerous randomized trials, the provisional approach of implanting one stent on the main branch has became the default approach to most bifurcation lesions. Dedicated bifurcation stents have been designed to specifically address some of the shortcomings of the conventional percutaneous approach to bifurcation intervention. The majority of the devices are aimed at facilitating the provisional approach. Dedicated bifurcation stents should enable all operators to treat the side-branch ostium simultaneously with the main branch, preserving a safe, permanent access to side branch during the procedure. In the future, the use of these new devices will probably enhance the interaction between adequate mechanical scaffolding and accurate delivery of the appropriate dosage of any new antirestenosis drugs. There are currently 11 devices available that either have completed or are undergoing first-in-man trials. The development of further drug-eluting platforms and larger controlled studies should demonstrate their clinical applicability, efficacy, and safety before they are widely incorporated into daily practice.

Background: Optimal treatment strategy of patients with ST elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD) undergoing primary angioplasty is still unclear. Percutaneous coronary intervention (PCI) of non-culprit vessels simultaneously or soon after primary angioplasty is feasible and safe, but available data failed to consistently show a benefit in long-term clinical outcomes. Methods: We retrospectively compared in-hospital and long-term outcomes for patients with STEMI and multivessel CAD treated by primary angioplasty with (Group 1, n=64) or without (Group 2, n=46) early, staged PCI of other angiographically significant coronary lesions. In-hospital major adverse cardiovascular events (MACE) were defined as a composite of death, peri-procedural myocardial infarction after staged, elective PCI, stroke, stent thrombosis, major bleeding, and vascular complications. MACE at follow-up were defined as a composite of death, stroke, stent thrombosis, any coronary revascularization, and re-hospitalization for acute coronary syndrome. Results: Group 1 patients underwent staged PCI 5.9 ± 3.5 days after primary angioplasty. The mean length of follow-up was 13 months (392 ± 236 days). The incidence of in-hospital MACE was 20.3% in Group 1 and 10.8% in Group 2 (P=0.186); the incidence of out of hospital MACE was 9.3% in Group 1 and 23.9% in Group 2 (P=0.037). In Group 1 in-hospital MACE were driven by periprocedural myocardial infarction after the elective procedure, which occurred in 15.6% of patients. Conclusions: Our data show that multivessel, staged PCI in STEMI patients is associated with a low incidence of adverse events at follow-up but with a higher incidence of in-hospital MACE, mainly driven by periprocedural myocardial infarction during the elective procedure. (J Interven Cardiol 2007;**:1‐7)

Background: Late percutaneous coronary intervention (PCI) of a totally occluded infarct-related artery (IRA) in stable patients is currently not recommended based on the lack of clear clinical benefits in randomized controlled trials. We sought to perform a systematic review and meta-analysis of randomized controlled trials comparing PCI with optimal medical therapy in patients with IRA occlusion more than 12 hr after onset of acute myocardial infarction (AMI), focusing on left ventricular function and remodeling. Methods and Results: PubMed, CENTRAL, and mRCT were searched for eligible studies. Studies were included in the analysis if they were randomized controlled trials comparing conservative medical management with PCI performed at least 12 hr after the onset of symptoms of AMI, and data on left ventricular ejection fraction (LVEF) at baseline and follow-up were available. Studies were excluded if randomization occurred less than 12 hr after symptom onset, or if patients were hemodynamically unstable. Change in LVEF was the primary outcome of interest, with changes in left ventricular end-diastolic volume index (LVEDVI) and end-systolic volume index (LVESVI) analyzed as secondary endpoints. We retrieved five studies in which baseline and follow up LVEF data were available enrolling a total of 648 patients: 342 patients randomized to PCI and 306 to medical treatment. There was a statistically significant difference in LVEF changes over time favoring PCI (13.1%, 95% CI 11.0 to 15.2, P 5 0.0004). In addition, there were statistically significant differences changes in both LVEDVI (25.1 ml in favor of PCI, 95% CI of 29.4 to 20.8, P 5 0.020) and LVESVI (25.3 ml in favor in PCI, 95% CI of 28.3 to 22.4, P 5 0.0005). Conclusions: This metaanalysis suggests that late revascularization of an occluded IRA may improve left ventricular systolic function and remodeling, supporting the ‘‘open artery hypothesis.’’ The reason why these changes have not resulted in clinical benefits in large clinical trials is

Background Infarct-related artery (IRA) patency after acute myocardial infarction (AMI) is associated with a more favourable clinical course, in particular in patients with high-risk features. As it has been recently reported that IRA patency is associated with a reduced postinfarction apoptotic rate (AR), the aim of our study was to assess whether IRA status late after AMI had a different impact on AR in high- vs. low-risk patients. Methods and results Co-localization of TUNEL and caspase-3 was used to calculate the AR at the site of infarction at the time of death in 30 subjects. The Norris coronary prognostic index (NI) was calculated (computing age, presence of pulmonary congestion, heart size and history of previous additional AMI) in order to define the patients’ individual risk at the time of hospitalization. According to the NI (≤ 7 vs. > 7), subjects were divided into low and high risk, as NI > 7 carries an approximate threefold higher risk of death. The NI was significantly correlated with the AR at the time of death both in infarct and remote areas. Twenty subjects had IRA occlusion at the time of death, and in these patients AR was significantly higher both in infarct and remote areas (P

Left ventricular (LV) remodeling and heart failure (HF) complicate acute myocardial infarction (AMI) even weeks to months after the initial insult. Apoptosis may represent an important pathophysiologic mechanism causing progressive myocardiocyte loss and LV dilatation even late after AMI. This review will discuss the role of apoptosis according to findings in animal experimental data and observational studies in humans in order to assess clinical relevance, determinants, and mechanisms of myocardial apoptosis and potential therapeutic implications. More complete definition of the impact of myocardiocyte loss on prognosis and of the mechanisms involved may lead to improved understanding of cardiac remodeling and possibly improved patients' care. Mitochondrial damage and bcl-2 to bax balance play a central role in ischemia-dependent apoptosis while angiotensin II and β1-adrenergic-stimulation may be major causes of receptormediated apoptosis. Benefits due to treatment with ACE-inhibitors and β-blockers appear to be in part due to reduced myocardial apoptosis. Moreover, infarct-related artery patency late after AMI may be a major determinant of myocardial apoptosis and clinical benefits deriving from an open artery late post AMI (the "open artery hypothesis") may be, at least in part, due to reduced myocardiocyte loss. © 2002 Wiley-Liss, Inc.