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Background: The prevalence of depression is high in cardiac patients. Depression has a significant impact on quality of life, adherence to therapy, and an independent effect on prognosis. The Cardiac Depression Scale (CDS) is the only instrument designed to measure depression in cardiac patients. This study systematically reviewed the psychometric properties of the CDS for screening of depression in patients with coronary heart disease (CHD). Methods: A search of MEDLINE, EMBASE, CINAHL Plus, PsycINFO, Scopus and Web of Science was performed using the search term Cardiac Depression Scale in the title or abstract. Eligible studies were those that assessed reliability, validity or diagnostic accuracy of the CDS in patients with CHD. Methodological quality was assessed using the QUADAS-2 and STARD. Results: Most studies assessed the reliability and validity of the CDS: three studies assessed construct validity using factor analysis; six studies assessed the validity of the CDS with other measures of depression; and four studies assessed its diagnostic accuracy. However, some studies reported overlapping samples, which reduces confidence in their evaluation. Conclusion: This review finds the CDS to be a psychometrically sound measurement instrument for identifying mild, moderate and severe depression in cardiac populations. [Copyright &y& Elsevier]

Highlights: [•] Patients developing UAP had overall more atherosclerosis as patients without any events. [•] Patients developing MACE had only more mixed plaque as those developing UAP. [•] Different atherosclerotic plaque components by CTA carry different prognostic value. [Copyright &y& Elsevier]

Abstract: Many current pharmaceutical therapies for systolic heart failure target intracellular [Ca2+] ([Ca2+]i) metabolism, or cardiac troponin C (cTnC) on thin filaments, and can have significant side-effects, including arrhythmias or adverse effects on diastolic function. In this study, we tested the feasibility of directly increasing the Ca2+ binding properties of cTnC to enhance contraction independent of [Ca2+]i in intact cardiomyocytes from healthy and myocardial infarcted (MI) hearts. Specifically, cardiac thin filament activation was enhanced through adenovirus-mediated over-expression of a cardiac troponin C (cTnC) variant designed to have increased Ca2+ binding affinity conferred by single amino acid substitution (L48Q). In skinned cardiac trabeculae and myofibrils we and others have shown that substitution of L48Q cTnC for native cTnC increases Ca2+ sensitivity of force and the maximal rate of force development. Here we introduced L48Q cTnC into myofilaments of intact cardiomyocytes via adeno-viral transduction to deliver cDNA for the mutant or wild type (WT) cTnC protein. Using video-microscopy to monitor cell contraction, relaxation, and intracellular Ca2+ transients (Fura-2), we report that incorporation of L48Q cTnC significantly increased contractility of cardiomyocytes from healthy and MI hearts without adversely affecting Ca2+ transient properties or relaxation. The improvements in contractility from L48Q cTnC expression are likely the result of enhanced contractile efficiency, as intracellular Ca2+ transient amplitudes were not affected. Expression and incorporation of L48Q cTnC into myofilaments was confirmed by Western blot analysis of myofibrils from transduced cardiomyocytes, which indicated replacement of 18±2% of native cTnC with L48Q cTnC. These experiments demonstrate the feasibility of directly targeting cardiac thin filament proteins to enhance cardiomyocyte contractility that is impaired following MI. [Copyright &y& Elsevier]

Abstract: While inhibition of class I/IIb histone deacetylases (HDACs) protects the mammalian heart from ischemia reperfusion (IR) injury, class selective effects remain unexamined. We hypothesized that selective inhibition of class I HDACs would preserve left ventricular contractile function following IR in isolated hearts. Male Sprague Dawley rats (n =6 per group) were injected with vehicle (dimethylsulfoxide, 0.63mg/kg), the class I/IIb HDAC inhibitor trichostatin A (1mg/kg), the class I HDAC inhibitor entinostat (MS-275, 10mg/kg), or the HDAC6 (class IIb) inhibitor tubastatin A (10mg/kg). After 24h, hearts were isolated and perfused in Langendorff mode for 30min (Sham) or subjected to 30min global ischemia and 120min global reperfusion (IR). A saline filled balloon attached to a pressure transducer was placed in the LV to monitor contractile function. After perfusion, LV tissue was collected for measurements of antioxidant protein levels and infarct area. At the conclusion of IR, MS-275 pretreatment was associated with significant preservation of developed pressure, rate of pressure generation, rate of pressure relaxation and rate pressure product, as compared to vehicle treated hearts. There was significant reduction of infarct area with MS-275 pretreatment. Contractile function was not significantly restored in hearts treated with trichostatin A or tubastatin A. Mitochondrial superoxide dismutase (SOD2) and catalase protein and mRNA in hearts from animals pretreated with MS-275 were increased following IR, as compared to Sham. This was associated with a dramatic enrichment of nuclear FOXO3a transcription factor, which mediates the expression of SOD2 and catalase. Tubastatin A treatment was associated with significantly decreased catalase levels after IR. Class I HDAC inhibition elicits protection of contractile function following IR, which is associated with increased expression of endogenous antioxidant enzymes. Class I/IIb HDAC inhibition with trichostatin A or selective inhibition of HDAC6 with tubastatin A was not protective. This study highlights the need for the development of new strategies that target specific HDAC isoforms in cardiac ischemia reperfusion. [Copyright &y& Elsevier]

Abstract: The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer. [Copyright &y& Elsevier]

Objective: The loss of normal apical rotation is associated with left ventricular (LV) remodeling and systolic dysfunction in patients with congestive heart failure after myocardial infarction. The objective of the present study was to evaluate the effect of epicardial ventricular reconstruction, an off-pump, less-invasive surgical reshaping technique, on myocardial strain, LV twist, and the potential alteration of myocardial fiber orientation in an ovine model of LV anteroapical aneurysm. Methods: LV anteroapical myocardial infarction was induced by coil embolization of the left anterior descending artery. Eight weeks after occlusion, epicardial ventricular reconstruction was performed using left thoracotomy under fluoroscopic guidance in 8 sheep to completely exclude the scar. The peak systolic longitudinal/circumferential strains and LV twist were evaluated using speckle tracking echocardiography before (baseline), after device implantation, and at 6 weeks of follow-up. Results: Epicardial ventricular reconstruction was completed in all sheep without any complications. Immediately after device implantation, LV twist significantly increased (4.18 ± 1.40 vs baseline 1.97 ± 1.92; P = .02). The ejection fraction had increased 17% and LV end-systolic volume had decreased 40%. The global longitudinal strain increased from −5.3% to −9.1% (P < .05). Circumferential strain increased in both middle and apical LV segments, with the greatest improvement in the inferior lateral wall (from −11.4% to −20.6%, P < .001). These effects were maintained ≥6 weeks after device implantation without redilation. Conclusions: Less invasive than alternative therapies, epicardial ventricular reconstruction on the off-pump beating heart can restore LV twist and systolic strain and reverse LV remodeling in an ovine anteroapical aneurysm model. [Copyright &y& Elsevier]

Background: Certain types of the early repolarization phenomenon, previously considered to be benign, have been reported to be associated with ventricular fibrillation (VF), both in population-based studies and in the myocardial infarction (MI) settings. Objective: To analyze whether QRS widening and appearance of a J-wave pattern in experimental MI settings is predictive of VF. Methods: MI was induced in 32 pigs by 40-minute inflation of an angioplasty balloon in the left descending artery, and electrocardiogram was continuously recorded. Multilead QRS boundaries were computed, and QRS duration was calculated on a beat-to-beat basis during the occlusion period for each pig. An association between QRS widening and subsequent VF was studied using receiver operating characteristic curve analysis. Electrocardiograms at maximum QRS duration were reviewed for the presence of a J-wave pattern. Results: Sixteen animals had VF episodes during the occlusion period. Two peaks of QRS widening were found in all animals: the first peak immediately on left descending artery occlusion and the second peak 19.1 ± 4.0 minutes later. The magnitude of changes in the QRS width over time had significant interindividual differences. A QRS widening of ≥28 ms during a 3-minute time window was observed in 14 animals and predicted impending VF (selectivity 80%, specificity 73%, positive predictive value 57%, and negative predictive value 89%; P = .008). In 10 of 14 (71%) pigs, a J-wave pattern appeared at maximal QRS duration. The appearance of a J-wave pattern predicted VF with selectivity 80%, specificity 68%, positive predictive value 53%, and negative predictive value 88% (P = .02). Conclusion: Transient QRS widening, commonly associated with a J-wave pattern, appears to predict impending VF in acute ischemia settings and motivates further clinical studies for monitoring immediate risk of VF in MI. [Copyright &y& Elsevier]

Background: Postoperative atrial fibrillation (POAF) is considered to be a transient arrhythmia in the first week after cardiac surgery. Objective: To determine the 30-day incidence and predictors of POAF and the value of postoperative overdrive biatrial pacing in the prevention of POAF. Methods: Patients (n = 148) without a history of atrial fibrillation undergoing aortic valve replacement or coronary artery bypass graft (CABG) were randomized into a pacing group (n = 75) and a control group. Patients were treated with standardized sotalol postoperatively. Rhythm was continuously monitored for 30 days by a transtelephonic event recorder. Results: POAF occurred in 73 (49.3%) patients, of whom 60 (40.5%) patients showed POAF during postoperative days (PODs) 0–5 and 37 (25%) patients during PODs 6–30. Prolonged aortic cross-clamp time was an important univariate predictor of 30-day and of late POAF (PODs 6–30; P = .017 and P = .03, respectively). Best-fit model analysis using 15 predetermined risk factors for POAF showed different positive interactive effects for early POAF (ie, baseline C-reactive protein levels with a history of myocardial infarction or low body mass index) and late POAF (ie, high body mass index, diabetes mellitus, baseline C-reactive protein, early POAF, creatinine levels, type of operation, smoking, and male gender). Biatrial pacing reduced the late POAF incidence in patients with aortic cross-clamp time >50 minutes (P = .006). Conclusion: POAF is not limited to the first week after cardiac surgery but also occurs frequently in the postoperative month. It is desirable to regularly follow patients with POAF for atrial fibrillation recurrences after discharge. [Copyright &y& Elsevier]

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Abstract: Objective: The purpose of this work was to meta-analyze prospective studies that have evaluated the effect of a Mediterranean diet on the development of type 2 diabetes. Materials/Methods: PubMed, Embase and the Cochrane Central Register of Controlled Trials databases were searched up to 20 November 2013. English language publications were allocated; 17 original research studies (1 clinical trial, 9 prospective and 7 cross-sectional) were identified. Primary analyses were limited to prospective studies and clinical trials, yielding to a sample of 136,846 participants. A systematic review and a random effects meta-analysis were conducted. Results: Higher adherence to the Mediterranean diet was associated with 23% reduced risk of developing type 2 diabetes (combined relative risk for upper versus lowest available centile: 0.77; 95% CI: 0.66, 0.89). Subgroup analyses based on region, health status of participants and number of confounders controlling for, showed similar results. Limitations include variations in Mediterranean diet adherence assessment tools, confounders’ adjustment, duration of follow up and number of events with diabetes. Conclusions: The presented results are of major public health importance, since no consensus exists concerning the best anti-diabetic diet. Mediterranean diet could, if appropriately adjusted to reflect local food availability and individual’s needs, constitute a beneficial nutritional choice for the primary prevention of diabetes. [Copyright &y& Elsevier]

Objectives: This study sought to evaluate if an undetectable (<5 ng/l) high-sensitivity cardiac troponin T (hs-cTnT) level and an electrocardiogram (ECG) without signs of ischemia can rule out myocardial infarction (MI) in the emergency department (ED). Background: Chest pain is a common symptom often associated with benign conditions, but may be a sign of MI. Because there is no rapid way to rule out MI, many patients are admitted to the hospital. Methods: All patients who sought medical attention for chest pain and had at least 1 hs-cTnT analyzed during 2 years at the Karolinska University Hospital, Stockholm, Sweden, were included. We calculated the negative predictive values of an undetectable hs-cTnT and ECG without ischemia for MI and death within 30 days. Results: We included 14,636 patients, of whom 8,907 (61%) had an initial hs-cTnT of <5 ng/l; 21% had 5 to 14 ng/l, and 18% had >14 ng/l. During 30-day follow-up, 39 (0.44%) patients with undetectable hs-cTnT had a MI, of whom 15 (0.17%) had no ischemic ECG changes. The negative predictive value for MI within 30 days in patients with undetectable hs-cTnT and no ischemic ECG changes was 99.8% (95% confidence interval [CI]: 99.7 to 99.9). The negative predictive value for death was 100% (95% CI: 99.9 to 100). Conclusions: All patients with chest pain who have an initial hs-cTnT level of <5 ng/l and no signs of ischemia on an ECG have a minimal risk of MI or death within 30 days, and can be safely discharged directly from the ED. [Copyright &y& Elsevier]

Objectives: This study sought to examine sex-related differences in outcomes related to peripheral vascular intervention (PVI) procedures. Background: Percutaneous PVI is frequently performed for the treatment of peripheral arterial disease (PAD). However, little is known about sex-related differences related to PVI procedures. Methods: We assessed the impact of sex among 12,379 patients (41% female) who underwent lower extremity (LE)-PVI from 2004 to 2009 at 16 hospitals participating in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium PVI registry. Multivariate propensity-matched analyses were performed to adjust for differences in baseline characteristics, procedural indications, and comorbidities on the basis of sex. Results: Compared with men, women were older and have multilevel disease and critical limb ischemia. In a propensity-matched analysis, female sex was associated with a higher rate of vascular complications, transfusions, and embolism. No differences were observed for in-hospital death, myocardial infarction, or stroke or transient ischemic attack. Technical success was more commonly achieved in women (91.2% vs. 89.1%, p = 0.014), but because of a higher complication rate, the overall procedural success rates were similar in men and women (79.7% vs. 81.6%, p = 0.08). Conclusions: Women represent a significant proportion of patients undergoing LE-PVI, have a more severe and complex disease process, and are at increased risk for adverse outcomes. Despite higher complications rates, women had similar procedural success compared with men, making PVI an effective treatment strategy among women with LE-PAD. [Copyright &y& Elsevier]

Objectives: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. Background: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. Methods: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. Results: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function. Conclusions: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558) [Copyright &y& Elsevier]

Objectives: This study sought to examine the effectiveness of clopidogrel in real-world, medically managed patients with unstable angina (UA) or non–ST-segment elevation myocardial infarction (NSTEMI). Background: Although clinical trials have demonstrated the efficacy of clopidogrel to reduce cardiovascular (CV) morbidity and mortality in medically managed patients with UA or NSTEMI, the effectiveness of clopidogrel in actual clinical practice is less certain. Methods: A retrospective cohort study was conducted of Kaiser Permanente Northern California members without known coronary artery disease or prior clopidogrel use who presented with UA or NSTEMI between 2003 and 2008 and were medically managed (i.e., no percutaneous coronary intervention or coronary artery bypass grafting during the index hospitalization or within 7 days post-discharge). Over 2 years of follow-up, we measured the association between clopidogrel use and all-cause mortality, hospital stay for MI, and a composite endpoint of death or MI using propensity-matched multivariable Cox analyses. Results: We identified 16,365 patients with incident UA (35%) or NSTEMI (65%); 36% of these patients were prescribed clopidogrel within 7 days of discharge. In 8,562 propensity score–matched patients, clopidogrel users had lower rates of all-cause mortality (8.3% vs. 13.0%; p < 0.01; adjusted hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.54 to 0.72) and the composite of death or MI (13.5% vs. 17.4%; p < 0.01; HR: 0.74, CI: 0.66 to 0.84), but not MI alone (6.7% vs. 7.2%; p = 0.30; HR: 0.93, CI: 0.78 to 1.11), compared with nonusers of clopidogrel. The association between clopidogrel use and the composite of death or MI was significant only among patients presenting with NSTEMI (HR: 0.67; CI: 0.59 to 0.76; pint < 0.01), not among those presenting with UA (HR: 1.25; CI: 0.94 to 1.67). Conclusions: In a large, community-based cohort of patients who were medically managed after UA/NSTEMI, clopidogrel use was associated with a lower risk of death and MI, particularly among patients with NSTEMI. [Copyright &y& Elsevier]

Objectives: This study sought to determine the capacity of cardiorespiratory fitness (CRF) algorithms without exercise testing to predict the risk for nonfatal cardiovascular disease (CVD) events and disease-specific mortality. Background: Cardiorespiratory fitness (CRF) is not routinely measured, as it requires trained personnel and specialized equipment. Methods: Participants were 43,356 adults (21% women) from the Aerobics Center Longitudinal Study, followed up between 1974 and 2003. Estimated CRF was determined on the basis of sex, age, body mass index, waist circumference, resting heart rate, physical activity level, and smoking status. Actual CRF was measured by a maximal treadmill test. Risk reduction per 1–metabolic equivalent increase, discriminative ability (c statistic), and net reclassification improvement were determined. Results: During a median follow-up of 14.5 years, 1,934 deaths occurred, 627 due to CVD. In a subsample of 18,095 participants, 1,049 cases of nonfatal CVD events were ascertained. After adjustment for potential confounders, both measured and estimated CRF were inversely associated with risks for all-cause mortality, CVD-related mortality and nonfatal CVD events in men, and all-cause mortality and nonfatal CVD events in women. The risk reduction per 1–metabolic equivalent increase ranged from approximately 10% to 20%. Measured CRF had a slightly better discriminative ability (c statistic) than did estimated CRF, and the net reclassification improvement values in measured CRF versus estimated CRF were 12.3% in men (p < 0.05) and 19.8% in women (p < 0.001). Conclusions: These CRF algorithms utilized information routinely collected to obtain an estimate of CRF, which provides a valid indication of health status. In addition to identifying people at risk, this method can provide more appropriate exercise recommendations that reflect initial CRF levels. [Copyright &y& Elsevier]

Objectives: The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis. Background: Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear. Methods: We searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events. Results: We identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n = 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = 5.6 × 10−11). We found no evidence for biases to account for these findings. Conclusions: Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD. [ABSTRACT FROM AUTHOR]

Over the last few years, the field of microribonucleic acid (miRNA) in cardiovascular biology and disease has expanded at an incredible pace. miRNAs are themselves part of a larger family, that of non-coding RNAs, the importance of which for biological processes is starting to emerge. miRNAs are ∼22-nucleotide-long RNA sequences that can legate messenger (m)RNAs at partially complementary binding sites, and hence regulate the rate of protein synthesis by altering the stability of the targeted mRNAs. In the cardiovascular system, miRNAs have been shown to be critical regulators of development and physiology. They control basic functions in virtually all cell types relevant to the cardiovascular system (such as endothelial cells, cardiac muscle, smooth muscle, inflammatory cells, and fibroblasts) and, thus, are directly involved in the pathophysiology of many cardiovascular diseases. As a result of their role in disease, they are being studied for exploitation in diagnostics, prognostics, and therapeutics. However, there are still significant obstacles that need to be overcome before they enter the clinical arena. We present here a review of the literature and outline the directions toward their use in the clinic. [Copyright &y& Elsevier]

Highlights: [•] One dose of oral hexarelin treatment potentially protects chronic cardiac function. [•] It can modulate autonomic nervous activity after myocardial infarction. [•] It implicates that activating GHSR 1a might be beneficial for cardioprotection. [Copyright &y& Elsevier]

Abstract: Thresholds for red blood cell transfusion following cardiac surgery vary by hospital and surgeon. The TITRe2 multi-centre randomised controlled trial aims to randomise 2000 patients from 17 United Kingdom centres, and tests the hypothesis that a restrictive transfusion threshold will reduce postoperative morbidity and health service costs compared to a liberal threshold. Patients consent to take part in the study pre-operatively but are only randomised if their haemoglobin falls below 9g/dL during their post-operative hospital stay. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first three months after randomisation. Many challenges have been encountered in the set-up and running of the study. [Copyright &y& Elsevier]

Abstract: Objectives: To compare the outcomes of initial one-stent (1S) versus dedicated two-stent (2S) strategies in complex bifurcation percutaneous coronary intervention (PCI) using everolimus-eluting stents (EES). Background: PCI of true bifurcation lesions is technically challenging and historically associated with reduced procedural success and increased restenosis. Prior studies comparing initial one-stent (1S) versus dedicated two-stent (2S) strategies using first-generation drug-eluting stents have shown no reduction in ischemic events and more complications with a 2S strategy. Methods: We performed a retrospective study of 319 consecutive patients undergoing PCI at a single referral center with EES for true bifurcation lesions, defined by involvement of both the main vessel (MV) and side branch (SB). Baseline, procedural characteristics, quantitative coronary angiography and clinical outcomes in-hospital and at one year were compared for patients undergoing 1S (n=175) and 2S (n=144) strategies. Results: Baseline characteristics were well-matched. 2S strategy was associated with greater SB acute gain (0.65±0.41mm vs. 1.11±0.47mm, p<0.0001). In-hospital serious adverse events were similar (9% with 2S vs. 8% with 1S, p=0.58). At one year, patients treated by 2S strategy had non-significantly lower rates of target vessel revascularization (5.8% vs. 7.4%, p=0.31), myocardial infarction (7.8% vs. 12.2%, p=0.31) and major adverse cardiovascular events (16.6% vs. 21.8%, p=0.21). Conclusion: In this study of patients undergoing PCI for true coronary bifurcation lesions using EES, 2S strategy was associated with superior SB angiographic outcomes without excess complications or ischemic events at one year. [Copyright &y& Elsevier]

Background The treatment of microcirculatory impairment will have great impact if it can be applied to myocardial infarction (MI) patients. The problem is how to study these tiny structures and microphenomenon in heart. Methods We investigated the visualization of cardiac microvessels embolization by the mean of X-ray phase contrast imaging (XPCI), which is a recently emerged imaging technique. Using the information of X-ray phase shift, it is sensitive to weak absorbing materials. Two MI SD rats were used as the microvessel embolization samples. MI was surgically induced by ligating left anterior descending artery. Imaging was performed 24 hours post-infarct, with barium sulfate as contrast agent. Results The coronary arteries were visualized with smooth walls and clear edges. The ligated vessels, with the diameter of about three hundred microns, can be clearly distinguished and there were no distal blood flow downstream from these branches. The results indicate that phase contrast imaging can directly demonstrate the distribution of microvessels, and estimate the area of MI. The infarct location was in good agreement with pathological analyses of the models. Conclusions The advantage of our method is directly observing and evaluating microvessel embolization which simplifies the procedure of diagnoses. Moreover, it is helpful for predicting the prognosis in MI and judging if angiogenesis happens. [ABSTRACT FROM AUTHOR]

Abstract: Cell proliferation from pre-existing cardiomyocytes is a major source of cells for normal mammalian myocardial renewal or for regeneration after myocardial injury. These proliferative cardiomyocytes may act differently from the postmitotic cardiomyocytes in a stressed heart. Extracellular matrix molecule CCN1 is produced to promote Fas ligand (FasL)-induced cardiomyocyte apoptosis in mice with stress-induced cardiac injury. We aimed to investigate the effect of CCN1 on the proliferative cardiomyocytes. We used rat embryonic cardiomyoblast H9c2 cells to study the cardiotoxicity of CCN1. We found that FasL dose-dependently increased the X-linked inhibitor of apoptosis protein (XIAP) levels to prevent the progression of apoptosis in H9c2 cells. CCN1, though it did not induce apoptosis by itself, sensitized H9c2 cells to FasL-induced apoptosis. CCN1 functions by engaging its cell-surface receptor integrin α6β1 and elevating reactive oxygen species levels, which leads to mitogen-activated protein kinase p38 activation, cytosolic Bax translocation to mitochondria, and the release of mitochondrial Smac and HtrA2 to cytosol. These elevated cytosolic Smac and HtrA2 dismantle the inhibition of XIAP, thereby facilitating the activation of caspase-3 and the apoptosis-induced by FasL. In summary, we demonstrated a novel mechanism underlying the resistance of cardiomyoblasts to FasL-induced apoptosis, and the pro-apoptotic function of CCN1 by disrupting this resistance. [Copyright &y& Elsevier]

Abstract: Cardiovascular disease is the primary cause of morbidity and mortality among the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. ‘Diabetic cardiomyopathy’ is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress as a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin–angiotensin–aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population. [Copyright &y& Elsevier]

Objectives: This study sought to investigate the prognostic value of access site bleeding (ASB) and non-ASB for recurrent ischemic outcomes and mortality in patients with ST-segment elevation myocardial infarction (STEMI). Background: The prognostic value of ASB-related complications after STEMI is subject to debate. Methods: The prognostic value of ASB and non-ASB for 1-year mortality, recurrent myocardial infarction (MI), stent thrombosis, and stroke was investigated in 2,002 STEMI patients undergoing primary percutaneous coronary intervention. In addition, we performed a meta-analysis of studies investigating the prognostic value of ASB and non-ASB in patients undergoing percutaneous coronary intervention. Results: Seventy-four patients (3.7%) were treated by radial access. ASB developed in 124 patients (6.3%) and non-ASB developed in 102 (5.2%). By multivariable analysis, ASB was not associated with a higher risk of 1-year mortality (hazard ratio [HR]: 1.03; p = 0.89), recurrent MI (HR: 1.16; p = 0.64), stent thrombosis (HR: 0.55; p = 0.42), or stroke (HR: 0.47; p = 0.31). Non-ASB was independently associated with 1-year mortality (HR: 2.77; p < 0.001) and stent thrombosis (HR: 3.10; p = 0.021), but not with recurrent MI and stroke. In a meta-analysis including 495,630 patients, non-ASB was associated with a greater adjusted risk of subsequent 1-year mortality than ASB (HR: 1.66; 95% CI: 1.56 to 1.76 and HR: 1.21; 95% CI: 1.11 to 1.31). Conclusions: In STEMI, ASB was not significantly associated with 1-year clinical outcomes, whereas non-ASB was significantly associated with 1-year mortality and stent thrombosis. These results taken together with those of previous studies indicate a greater risk of subsequent mortality in patients with non-ASB. [Copyright &y& Elsevier]

Objective: This study sought to evaluate the prognostic value of routine stress myocardial perfusion scintigraphy (MPS) 5 years after percutaneous coronary intervention (PCI). Background: Current appropriate use criteria define routine cardiac stress imaging <2 years after PCI as inappropriate and >2 years as uncertain in asymptomatic patients. Methods: All 339 of 683 BASKET (Basel Stent Kosteneffektivitäts Trial) 5-year survivors (55%) consenting to undergo protocol-mandated MPS and subsequent evaluation irrespective of symptoms were followed for major adverse cardiac events (MACE) (cardiac death, myocardial infarction [MI], or revascularization). For MPS, summed perfusion scores were calculated and perfusion defects were related to treated-vessel or remote myocardial areas. Results: Patients were 72 ± 10 years of age, 18% were female, and 90% were free of angina. MPS findings were abnormal in 205 of 339 patients (60%) with complete follow-up. During 3.7 ± 0.3 years, there were 7 cardiac deaths, 18 MIs, and 47 revascularizations, resulting in a MACE rate of 4.4% and a cardiac mortality rate of 0.6% per year. Patients with abnormal MPS findings had higher hazard ratios (HR) for MACE (HR: 1.95; 95% confidence interval [CI]: 1.06 to 3.59; p = 0.032), and cardiac death/MI (HR: 2.50; 95% CI: 0.93 to 6.69; p = 0.066) than patients with normal MPS finding. MACE rates were similar in patients with symptomatic and silent ischemia (p = 0.61) but higher than in patients with normal MPS findings (p < 0.05 for both comparisons). MACE rates were independently predicted by remote ischemia but not by treated-vessel ischemia or scar. Conclusions: Abnormal MPS findings 5 years after PCI are frequent irrespective of symptoms. The predictive power of abnormal MPS lies more in the detection of persistent or progressing coronary artery disease in remote vessel areas than in the diagnosis of late intervention-related problems in treated vessels. [Copyright &y& Elsevier]

Objectives: This study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI). Background: Treatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI. Methods: STEMI patients in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events. Results: Reductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96). Conclusions: The efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591) [Copyright &y& Elsevier]

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with ≥10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that ≥10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, ≥3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by ≥4 of 32 stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions. [Copyright &y& Elsevier]

Objectives: The goal of this study was to determine the long-term prognostic value of coronary computed tomography angiography (CTA) in a large coronary artery bypass graft (CABG) population. Background: Coronary CTA has shown prognostic utility in patients without previous revascularization. However, prognostication with coronary CTA in CABG patients has not been fully assessed. Methods: Between March 2005 and April 2009, 887 consecutive CABG patients (mean age 66.8 ± 8.4 years) were considered for the inclusion in the study. Patients were classified by the number of unprotected coronary territories (UCTs) and a summary of native vessel disease and graft patency: the coronary artery protection score (CAPS). A primary endpoint (cardiovascular [CV] death, nonfatal myocardial infarction [MI]) and a secondary combined adverse events endpoint (CV death, MI, unstable angina, and late revascularizations) were recorded. Results: Among the 887 evaluated, 166 did not meet the inclusion criteria. The final study population consisted of 721 subjects. Ten patients were excluded for unevaluable coronary CTA images. Of the remaining 711 patients, follow-up (mean 73.5 ± 14 months) was obtained in 698. Three hundred forty-seven events were recorded. By univariable analysis, the strongest coronary CTA predictors of events were UCT 2 and 3 (hazard ratio [HR] for CV death/MI: 7.5 and 10.19, p < 0.0001 and p < 0.0003, respectively) and CAPS 4 (HR for CV death/MI: 24.1, p < 0.0001). A high number of UCTs was also a strong multivariable independent predictor of CV death/MI (HR: 7.78 and 10.18 for UCT 2 and 3, p < 0.0001 and p < 0.0007, respectively). Cumulative survival rates for CV death/MI and composite adverse CV events were 86% and 73% with UCT 0, 84% and 49% with UCT 1, 53% and 3% with UCT 2, and 29% and 0% with UCT 3, respectively. Conclusions: Coronary CTA appears to be a promising tool for long-term risk stratification of CABG patients. The UCT score has significant prognostic value to predict CV deaths/MI. [Copyright &y& Elsevier]

Background: Antiarrhythmic drugs (AADs) and anticoagulation are mainstays of atrial fibrillation (AF) treatment. Objective: To study the use and outcomes of AAD therapy in anticoagulated patients with AF. Methods: Patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial (N = 14,264) were stratified by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across AAD groups as well as across treatment assignment (rivaroxaban or warfarin). Results: Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone and 537 [3.8%] with other AADs). Amiodarone-treated patients were less often female (38% vs 48%), had more persistent AF (64% vs 40%), and more concomitant heart failure (71% vs 41%) than were patients receiving other AADs. Patients receiving no AAD more closely resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone than in those receiving no AAD (50% vs 58%; P < .0001). Compared with no AAD, neither amiodarone (adjusted hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.74–1.31; P = .9) nor other AADs (adjusted HR 0.66; 95% CI 0.37–1.17; P = .15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Treatment effects of rivaroxaban vs warfarin in patients receiving no AAD were consistent with results from the overall trial (primary end point: adjusted HR 0.82; 95% CI 0.68–0.98; P interaction = .06; safety end point: adjusted HR 1.12; 95% CI 0.90–1.24; P interaction = .33). Conclusion: Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The effect of amiodarone on outcomes in patients receiving rivaroxaban requires further investigation. [Copyright &y& Elsevier]

Objectives: The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background: High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods: A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results: Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score ≥8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score ≥8.0 versus <2.0. Conclusions: Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate whether baseline lesion complexity affects drug-eluting stent (DES) outcomes according to diabetic status. Background: Previous studies have reported conflicting results regarding DES safety and efficacy in patients with and without diabetes mellitus (DM). Methods: Patient-level data from 18 prospective randomized trials were pooled. DES treatment outcomes in patients with versus without DM were analyzed in 2 propensity score–matched groups further stratified according to lesion complexity (American College of Cardiology and American Heart Association class A/B1 vs. B2/C). Remaining baseline differences were adjusted for by multivariate analysis. Results: DM was present in 3,467 of 18,441 patients (18.8%). DM was a predictor of 1-year repeat revascularization (target lesion revascularization: hazard ratio: 1.34; 95% confidence interval: 1.05 to 1.70; target vessel revascularization: hazard ratio: 1.40; 95% confidence interval: 1.15 to 1.72) and cardiac death or myocardial infarction (hazard ratio: 1.40; 95% confidence interval: 1.09 to 1.81). Rates of target lesion and target vessel revascularization were significantly higher in patients with versus those without DM with type B2/C lesions (8.0% vs. 4.5% and 10.6% vs. 5.9%, respectively, p < 0.0001 for both), but not in patients with only type A/B1 lesions (4.6% vs. 4.8%, p = 0.87, and 7.4% vs. 6.8%, p = 0.47, respectively), with a significant interaction between DM and lesion type observed for both endpoints (p = 0.01 and p = 0.02, respectively). No interaction was observed for death or myocardial infarction (p = 0.28). Conclusions: In the DES era, patients with DM remain at increased risk for cardiac death or myocardial infarction. However, DM is a risk factor for repeat revascularization only in those patients with complex lesions; patients with DM and noncomplex lesions have similar rates of 1-year freedom from repeat revascularization as do patients without DM. [Copyright &y& Elsevier]

Supply/demand (type 2) myocardial infarction is a commonly encountered clinical challenge. It is anticipated that it will be detected more frequently once high-sensitivity cardiac troponin assays are approved for clinical use in the United States. We provide a perspective that is based on available data regarding the definition, epidemiology, etiology, pathophysiology, prognosis, management, and controversies regarding type 2 myocardial infarction. Understanding these basic concepts will facilitate the diagnosis and treatment of these patients as well as ongoing research efforts. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cardiac non-genomic and genomic estrogen receptor signaling is reviewed. [•] Hormone replacement controversies and cardiac outcomes are identified. [•] Experimental models of age-associated estrogen loss are described. [•] Defective estrogen signaling contributes to cardiac ischemic injury with aging. [•] Cardioprotective targets in the aged heart include heat shock proteins and PKC. [ABSTRACT FROM AUTHOR]

Cardiovascular disease continues to be the leading cause of death in the western world. Due to advancements in diagnosis, prevention, and treatment, cardiovascular mortality has fallen in recent years. Previous studies have evaluated the impact of traditional risk factors such as hypercholesterolemia and smoking. However, limited studies have been conducted to evaluate sex discrepancies among patients with cardiovascular disease. Pre-eclampsia is a multisystem placentally mediated disease, which usually arises after 32 weeks of gestation and classically presents with hypertension and proteinuria. Pre-eclampsia affects 2% to 8% of all pregnancies worldwide and is often complicated by fetal growth restriction. Women with a history of pre-eclampsia are at increased risk of future cardiovascular complications. Therefore, this topic is of significance to the cardiovascular health of over 300 million women worldwide. The goal of this review is to determine the association of pre-eclampsia and future cardiovascular risk and to explore the potential management options for these high-risk women. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a). Background: OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators. Methods: IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(−). Results: Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio [OR]: 2.84; p = 0.001). This effect was accentuated in patients age ≤60 years (OR: 7.03; p < 0.001). In IL-1(−) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(−) group in patients age ≤60 years but not in those age >60 years. In IL-1(+) patients age ≤60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006). Conclusions: Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events. [Copyright &y& Elsevier]

Coronary artery calcification (CAC) is a risk factor for adverse outcomes in the general population and in patients with coronary artery disease. The pathogenesis of CAC and bone formation share common pathways, and risk factors have been identified that contribute to the initiation and progression of CAC. Efforts to control CAC with medical therapy have not been successful. Event-free survival is also reduced in patients with coronary calcification after both percutaneous coronary intervention (PCI) and bypass graft surgery. Although drug-eluting stents and devices for plaque modification have modestly improved outcomes in calcified vessels, adverse event rates are still high. Innovative pharmacologic and device-based approaches are needed to improve the poor prognosis of patients with CAC. [Copyright &y& Elsevier]

Abstract: The success of clinical proteome analysis should be assessed based on the clinical impact following implementation of findings. Although there have been several technological advancements in mass spectrometry in the last years, these have not resulted in similar advancements in clinical proteomics. In addition, application of proteomic biomarkers in clinical diagnostics and practical improvement in the disease management is extremely rare. In this review, we discuss the relevant issues associated with identification of robust biomarkers of clinical value. Urine appears to be an ideal source of biomarkers, for theoretical, methodological, and practical reasons. Therefore, this review is focused on the search for biomarkers in urine within the last decade. Urine can be used for non-invasive assessment of a variety of diseases including those affecting the urogenital tract and also other pathologies such as cardiovascular disease or appendicitis. We also discuss the importance of data validation, an essential step in translating biomarkers into the clinical practice. Furthermore, we examine several examples of apparently successful proteomic biomarker discovery studies and their implications for disease diagnosis, prognosis, and therapy evaluation. We also discuss some current challenges in this field and reflect on future research prospects. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. [Copyright &y& Elsevier]

Objectives: This study investigated the safety profile and potential “therapeutic” effect of intravenous ultrasmall superparamagnetic iron-oxide (USPIO)-based iron administration regarding infarct healing in patients with ST-elevation myocardial infarction (STEMI). USPIO-administration was recently shown to enable an improved characterization of myocardial infarct pathology in acute STEMI patients. Materials and Methods: Seventeen study patients (IRON, 54±9yrs, 88% male) and 22 matched controls (CONTROL, 57±9yrs, 77% male) both with primary reperfused STEMI underwent multi-parametric CMR studies in the first week and three months after acute MI. Only IRON patients received a single intravenous bolus of 510mg elemental iron as ferumoxytol (FerahemeTM) within four days following acute MI. Results: Three months later, all patients were alive and there were no adverse cardiac events. Significant improvement in left ventricular (LV) ejection fraction (IRON: 53±10% to 59±9%, p=0.002; CONTROL: 54±6% to 57±10%, p=0.005) as well as shrinkage of infarct size were seen in both groups at follow-up. There was a more pronounced decrease in infarct size in the IRON group (IRON: −10.3±5.4% vs. CONTROL: −7.0±8.4%, p=0.050) in addition to a significant decrease in both endocardial extent and prevalence of transmural infarctions in IRON but not in CONTROL patients. A significant decrease in LV end systolic volume was only seen in the IRON group (71±25mL to 59±25mL, p=0.002). Conclusions: Intravenous iron administration in acute STEMI patients seems to be associated with an improved infarct healing and a beneficial global left ventricular remodelling. These findings together with the good safety profile make USPIO-based iron administration a promising future candidate as a “diagnostic” and “therapeutic” adjunctive solution in acute MI management. [ABSTRACT FROM AUTHOR]

Abstract: Ischemic heart disease is the primary cause of death worldwide. The pathophysiological process of cardiovascular diseases is linked to atheromatous plaque formation, while plaque rupture releases thrombogenic elements, which lead to activation of platelets, blood clotting and formation of thrombi. Platelet inhibitors are used to prevent thrombosis. The present systematic review discusses the efficacy of prasugrel in terms of platelet inhibition potential and clinical prevention of cardiovascular outcomes. The balance between reduction of ischemic events as a measure of drug efficacy and the risk of bleeding is reviewed. Other adverse events observed in patients treated with this platelet inhibitor are discussed, including hematological complications, and cutaneous and hepatic idiosyncratic reactions. The complex relationship between prasugrel use and cancer promotion is also described. [Copyright &y& Elsevier]

Abstract: Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) have a significantly increased risk of cardiovascular disease (CVD). The reason for this is unclear but may be due, at least in part, to the failure of endothelial repair mechanisms. Over the last 15years there has been much interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD. In the circulation there are two distinct populations of cells; myeloid angiogenic cells (MACs) which augment repair by the paracrine secretion of angiogenic factors, and outgrowth endothelial cells (OECs) which are true endothelial progenitor cells (EPCs) and promote vasculogenesis by differentiating into mature endothelium. There are marked abnormalities in the number and function of these cells in patients with RA and SLE. Inflammatory cytokines including interferon-alpha (IFNα) and tumour-necrosis factor alpha (TNFα) both impair MAC and OEC function ex vivo and may therefore contribute to the CVD risk in these patients. Whilst administration of mononuclear cells, MACs and other progenitors has improved cardiovascular outcomes in the acute setting, this is not a viable option in chronic disease. The pharmacological manipulation of MAC/OEC function in vivo however has the potential to significantly improve endothelial repair and thus reduce CVD in this high risk population. [Copyright &y& Elsevier]

Abstract: Introduction: Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. Materials and Methods: All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50mcg/kg) compared to the high dose (≥50mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. Results: There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2mcg/kg (SD±9.5mcg/kg) in the low dose and 99.8mcg/kg (SD±64.7mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). Conclusions: No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. [Copyright &y& Elsevier]

Objectives: The ORBIT II (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) trial evaluated the safety and efficacy of the coronary Orbital Atherectomy System (OAS) to prepare de novo, severely calcified coronary lesions for stent placement. Background: Despite advances in interventional techniques, treatment of calcified coronary lesions remains a challenge. Stent placement in these lesions may result in stent underexpansion, malapposition, and procedural complications. Methods: ORBIT II is a prospective, multicenter, nonblinded clinical trial that enrolled 443 consecutive patients with severely calcified coronary lesions at 49 U.S. sites from May 25, 2010, to November 26, 2012. Investigators used the centrifugal action of the OAS diamond-coated crown to modify calcified lesions prior to stent placement. Results: The pre-procedure mean minimal lumen diameter of 0.5 mm increased to 2.9 mm after the procedure. The primary safety endpoint was 89.6% freedom from 30-day major adverse cardiac events compared with the performance goal of 83%. The primary efficacy endpoint (residual stenosis <50% post-stent without in-hospital major adverse cardiac events) was 88.9% compared with the performance goal of 82%. Stent delivery occurred successfully in 97.7% of cases with <50% stenosis in 98.6% of subjects. Low rates of in-hospital Q-wave myocardial infarction (0.7%), cardiac death (0.2%), and target vessel revascularization (0.7%) were reported. Conclusions: The ORBIT II coronary OAS trial met both the primary safety and efficacy endpoints by significant margins. Preparation of severely calcified plaque with the OAS not only helped facilitate stent delivery, but improved both acute and 30-day clinical outcomes compared with the outcomes of historic control subjects in this difficult-to-treat patient population. (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions [ORBIT II]; NCT01092416) [Copyright &y& Elsevier]

Objectives: This study sought to compare the efficacy of coronary artery bypass graft surgery (CABG) to that of percutaneous coronary intervention (PCI) with first-generation drug-eluting stents among patients with multivessel disease (MVD), unprotected left main (LM) disease, and single-vessel proximal left anterior descending (LAD) disease. Background: The efficacy and safety of CABG versus PCI with drug-eluting stents in patient subgroups remains controversial. Methods: We systematically searched Cardiosource, Circulation, Clinicaltrials.gov, the Cochrane Library, EMBASE, and Medline for articles published through June 2013 for randomized controlled trials comparing CABG with PCI. Primary endpoints included mortality, myocardial infarction, revascularization, and stroke. Data were meta-analyzed with random-effects models. Results: We identified 7 randomized controlled trials (N = 5,835): 2 of MVD (n = 2,410, 100% diabetic), 2 of LM disease (n = 1,206, 29.0% diabetic), 1 of 3-vessel or LM disease (n = 1,900, 25.5% diabetic), and 2 of single-vessel proximal LAD disease (n = 319, 36.3% diabetic). In MVD patients, CABG reduced the risk of mortality (risk ratio [RR]: 0.70, 95% confidence interval [CI]: 0.57 to 0.87), myocardial infarction (RR: 0.47, 95% CI: 0.36 to 0.61), and repeat revascularization (RR: 0.36, 95% CI: 0.24 to 0.52), but increased stroke risk (RR: 1.72, 95% CI: 1.02 to 2.90). In patients with LM disease, CABG reduced revascularization risk (RR: 0.60, 95% CI: 0.46 to 0.78) and increased stroke risk (RR: 2.89, 95% CI: 1.15 to 7.27). Data for patients with single-vessel proximal LAD disease were inconclusive. Conclusions: CABG is more efficacious than is PCI with first-generation drug-eluting stents in patients with LM and MVD, at the cost of increased rates of stroke. No conclusion can be drawn for patients with single-vessel proximal LAD disease. [Copyright &y& Elsevier]

Objectives: The aim of this study was to evaluate 1-year clinical outcomes of diabetic patients treated with the Absorb bioresorbable vascular scaffold (BVS). Background: Clinical outcomes of diabetic patients after BVS implantation have been unreported. Methods: This study included 101 patients in the ABSORB Cohort B trial and the first consecutive 450 patients with 1 year of follow-up in the ABSORB EXTEND trial. A total of 136 diabetic patients were compared with 415 nondiabetic patients. In addition, 882 diabetic patients treated with everolimus-eluting metal stents (EES) in pooled data from the SPIRIT trials (SPIRIT FIRST [Clinical Trial of the Abbott Vascular XIENCE V Everolimus Eluting Coronary Stent System], SPIRIT II [A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System], SPIRIT III [Clinical Trial of the XIENCE V Everolimus Eluting Coronary Stent System (EECSS)], SPIRIT IV Clinical Trial [Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System]) were used for the comparison by applying propensity score matching. The primary endpoint was a device-oriented composite endpoint (DoCE), including cardiac death, target vessel myocardial infarction, and target lesion revascularization at 1-year follow-up. Results: The cumulative incidence of DoCE did not differ between diabetic and nondiabetic patients treated with the BVS (3.7% vs. 5.1%, p = 0.64). Diabetic patients treated with the BVS had a similar incidence of the DoCE compared with diabetic patients treated with EES in the matched study group (3.9% for the BVS vs. 6.4% for EES, p = 0.38). There were no differences in the incidence of definite or probable scaffold/stent thrombosis (0.7% for both diabetic and nondiabetic patients with the BVS; 1.0% for diabetic patients with the BVS vs. 1.7% for diabetic patients with EES in the matched study group). Conclusions: In the present analyses, diabetic patients treated with the BVS showed similar rates of DoCEs compared with nondiabetic patients treated with the BVS and diabetic patients treated with EES at 1-year follow-up. (ABSORB Clinical Investigation, Cohort B; NCT00856856; ABSORB EXTEND Clinical Investigation; NCT01023789; Clinical Trial of the Abbott Vascular XIENCE V Everolimus Eluting Coronary Stent System [SPIRIT FIRST]; NCT00180453; A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System [SPIRIT II]; NCT00180310; Clinical Trial of the XIENCE V Everolimus Eluting Coronary Stent System [EECSS] [SPIRIT III]; NCT00180479; Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System [SPIRIT IV Clinical Trial]; NCT00307047). [Copyright &y& Elsevier]

Objectives: This study sought to compare everolimus-eluting stents (EES) versus Resolute zotarolimus-eluting stents (ZES) in terms of patient- or stent-related clinical outcomes in an “all-comer” group of patients with diabetes mellitus (DM) who underwent percutaneous coronary intervention. Background: DM significantly increases the risk of adverse events after percutaneous coronary intervention. The efficacy and safety of second-generation drug-eluting stents, in particular EES versus ZES, in patients with DM have not been extensively evaluated. Methods: Patients with DM (1,855 of 5,054 patients, 36.7%) from 2 prospective registries (the EXCELLENT [Efficacy of Xience/Promus Versus Cypher in Reducing Late Loss After Stenting] registry and RESOLUTE-Korea [Registry to Evaluate the Efficacy of Zotarolimus-Eluting Stent]) who were treated with EES (n = 1,149) or ZES (n = 706) were compared. Stent-related outcome was target lesion failure (TLF), and patient-oriented composite events were a composite of all-cause mortality, any myocardial infarction, and any revascularization. Results: Despite a higher risk patient profile in the ZES group, both TLF (43 of 1,149 [3.7%] vs. 25 of 706 [3.5%], p = 0.899) and patient-oriented composite events (104 of 1,149 [9.1%] vs. 72 of 706 [10.2%], p = 0.416) were similar between the EES and ZES in patients with DM at 1 year. In those without DM, EES and ZES also showed comparable incidence of TLF (39 of 1,882 [2.1%] vs. 33 of 1,292 [2.6%], p = 0.370) and patient-oriented composite events (119 of 1,882 [6.3%] vs. 81 of 1,292 [6.3%], p = 0.951), which were all significantly lower than in the DM patients. These results were corroborated by similar findings from the propensity score-matched cohort. Upon multivariate analysis, chronic renal failure was the most powerful predictor of TLF in DM patients (hazard ratio: 4.39, 95% confidence interval: 1.91 to 10.09, p < 0.001). Conclusions: After unrestricted use of second-generation drug-eluting stents in all-comers receiving percutaneous coronary intervention, both EES and ZES showed comparable clinical outcomes in the patients with DM up to 1 year of follow-up. DM compared with non-DM patients showed significantly worse patient- and stent-related outcomes. Nonetheless, overall incidences of TLF were low, even in the patients with DM, suggesting excellent safety and efficacy of both types of second-generation drug-eluting stents in this high-risk subgroup of patients. [Copyright &y& Elsevier]

With advances in antiretroviral therapy (ART), individuals with human immunodeficiency virus (HIV) infection are living longer and increasingly die of non–HIV-related diseases, such as cardiovascular disease (CVD). Several observational studies suggest that HIV-infected patients on ART are at increased risk of CVD; however, the precise mechanisms underlying the association between HIV infection and CVD risk are uncertain. Atherosclerosis and arterial disease in HIV-infected individuals is a multifactorial process with several potential targets for research and therapeutic intervention. This paper critically reviews the contributions of imaging to our understanding of arterial disease, atherosclerosis, and CVD risk in HIV-infected individuals. In general, the findings of studies using carotid ultrasound, coronary computed tomographic angiography, and aortic positron emission tomography agree with those from observational studies of CVD events and suggest that HIV infection is associated with an increased risk of CVD. Observational studies of CVD outcomes and studies using carotid intima-media thickness suggest that there is a moderate increase in CVD risk related to HIV serostatus. Less can be said about the role of ART and specific ART therapies in CVD risk, mainly because imaging studies have had serious methodological limitations that diminish their generalizability. Brachial artery reactivity testing has been especially useful for elucidating the arterial pathophysiology of HIV infection and its treatments, as well as the arterial effects of interventions for treating HIV and dyslipidemia. Aortic positron emission tomography has been especially useful for evaluating arterial inflammation. Coronary artery calcium has not proven to be a useful marker of subclinical atherosclerosis in HIV-infected individuals. Imaging studies support the intriguing hypothesis that persistent inflammation and immune dysregulation contribute to increased CVD risk among treated and suppressed patients with HIV infection. [Copyright &y& Elsevier]

Objectives: This study sought to determine feasibility and prognostic performance of stress cardiac magnetic resonance (CMR) in obese patients (body mass index [BMI] ≥30 kg/m2). Background: Current stress imaging methods remain limited in obese patients. Given the impact of the obesity epidemic on cardiovascular disease, alternative methods to effectively risk stratify obese patients are needed. Methods: Consecutive patients with a BMI ≥30 kg/m2 referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death or nonfatal myocardial infarction. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes. Results: Of 285 obese patients, 272 (95%) completed the CMR protocol, and among these, 255 (94%) achieved diagnostic imaging quality. Mean BMI was 35.4 ± 4.8 kg/m2, with a maximum weight of 200 kg. Reasons for failure to complete CMR included claustrophobia (n = 4), intolerance to stress agent (n = 4), poor gating (n = 4), and declining participation (n = 1). Sedation was required in 19 patients (7%; 2 patients with intravenous sedation). Sixteen patients required scanning by a 70-cm–bore system (6%). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (0.3% vs. 6.3% for those with ischemia and 6.7% for those with ischemia and LGE). Median follow-up of the cohort was 2.1 years. In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, inducible ischemia (hazard ratio 7.5; 95% confidence interval: 2.0 to 28.0; p = 0.002) remained independently associated with MACE. When patients with early coronary revascularization (within 90 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE. Conclusions: Stress CMR is feasible and effective in prognosticating obese patients, with a very low negative event rate in patients without ischemia or infarction. [Copyright &y& Elsevier]

Abstract: Objectives: To translate, culturally adapt and psychometrically validate the Information Needs in Cardiac Rehabilitation (INCR) tool to Portuguese. Background: The identification of information needs is considered the first step to improve knowledge that ultimately could improve health outcomes. Methods: The Portuguese version generated was tested in 300 cardiac rehabilitation patients (CR) (34% women; mean age = 61.3 ± 2.1 years old). Test-retest reliability was assessed using intraclass correlation coefficient (ICC), the internal consistency using Cronbach's alpha, and the criterion validity was assessed with regard to patients' education and duration in CR. Results: All 9 subscales were considered internally consistent (á > 0.7). Significant differences between mean total needs and educational level (p < 0.05) and duration in CR (p = 0.03) supported criterion validity. The overall mean (4.6 ± 0.4), as well as the means of the 9 subscales were high (emergency/safety was the greatest need). Conclusion: The Portuguese INCR was demonstrated to have sufficient reliability, consistency and validity. [Copyright &y& Elsevier]

Background: Utilization rates (URs) for implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (PPSCD) are lacking in the community. Objective: The purpose of this study was to establish the ICD UR in central Indiana. Methods: A query run on 2 hospitals in a health information exchange database in Indianapolis identified patients between 2011 and 2012 with left ventricular ejection fraction (EF) ≤0.35. ICD eligibility and utilization were determined from chart review. Results: We identified 1863 patients with at least 1 low EF study. Two cohorts were analyzed: 1672 patients without and 191 patients with International Classification of Diseases, Ninth Revision, Clinical Modification procedure code 37.94 for ICD placement. We manually reviewed a stratified (by hospital) random sample of 300 patients from the no-ICD procedure code cohort and found that 48 (16%) had no ICD but had class I indications for ICD. Eight of 300 (2.7%) actually had ICD implantation for PPSCD. Review of all 191 patients in the ICD procedure code cohort identified 70 with ICD implantation for PPSCD. The ICD UR (ratio between patients with ICD for PPSCD and all with indication) was 38% overall (95% confidence interval [CI] 28%–49%). URs were 48% for males (95% CI 34%–61%), 21% for females (95% CI 16%–26%, P = .0002 vs males), 40% for whites (95% CI 27%–53%), and 37% for blacks (95% CI 28%–46%, P = .66 vs whites). Conclusion: ICD UR is 38% among patients meeting class I indications, suggesting further opportunities for improving guideline compliance. This study also illustrates limitations in calculating ICD UR using large electronic repositories without hands-on chart review. [Copyright &y& Elsevier]