Universitätsklinikum des Saarlandes

The ESC/ESH Guidelines represent the views of the ESC and ESH and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The ESC and ESH are not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC/ESH Guidelines and any other official

AIMS: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. CONCLUSION: Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

: Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

AIMS: Large randomized trials have shown that beta-blockers reduce mortality and hospital admissions in patients with heart failure. The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain. The SENIORS study was performed to assess effects of the beta-blocker, nebivolol, in patients >/=70 years, regardless of ejection fraction. METHODS AND RESULTS: We randomly assigned 2128 patients aged >/=70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction </=35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placebo. The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). Analysis was by intention to treat. Mean duration of follow-up was 21 months. Mean age was 76 years (SD 4.7), 37% were female, mean ejection fraction was 36% (with 35% having ejection fraction >35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). CONCLUSION: Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

RNA silencing processes are guided by small RNAs that are derived from double-stranded RNA. To probe for function of RNA silencing during infection of human cells by a DNA virus, we recorded the small RNA profile of cells infected by Epstein-Barr virus (EBV). We show that EBV expresses several microRNA (miRNA) genes. Given that miRNAs function in RNA silencing pathways either by targeting messenger RNAs for degradation or by repressing translation, we identified viral regulators of host and/or viral gene expression.

BACKGROUND: Untreated, one third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown. METHODS: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly. RESULTS: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk. CONCLUSIONS: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

1. INTRODUCTION 1.1 Principles The 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines continue to adhere to some fundamental principles that inspired the 2003 and 2007 guidelines, namely to base recommendations on properly conducted studies identified from an extensive review of the literature; to consider, as the highest priority, data from randomized, controlled trials and their meta-analyses, but not to disregard the results of observational and other studies of appropriate scientific calibre; and to grade the level of scientific evidence and the strength of recommendations in order to more effectively alert physicians on recommendations that are based on the opinions of the experts rather than on evidence (Tables 1 and 2). When appropriately recognized, this can avoid guidelines being perceived as prescriptive and favour the performance of studies wherein opinion prevails and evidence is lacking.TABLE 1: Classes of recommendationsTABLE 2: Levels of evidenceThis shortened version of the ESH/ESC guidelines is for the practicing physician who often requires simplified information. However, whenever the physicians would like to know the source of the data upon which the recommendations are based, they are encouraged to consult the extensive version of the ESH/ESC guidelines wherein adequate references are given. These guidelines, however, do not override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient. 1.2 New aspects Because of new evidence on several diagnostic and therapeutic aspects of hypertension, the present guidelines differ from the 2007 ones in several points: Re-emphasis on integration of blood pressure (BP), cardiovascular risk factors, asymptomatic organ damage and clinical complications for total cardiovascular risk assessment. Update of the prognostic significance of out-of-office BP (both ambulatory and home BP), white-coat hypertension and masked hypertension. Initiation of antihypertensive drug treatment only in patients with SBP or DBP values at least 140 or 90 mmHg, independent of level of total cardiovascular risk. Unified target SBP (<140 mmHg) in both higher and lower cardiovascular risk patients. Revised recommendations on treatment of hypertension in young people and in the elderly. Liberal approach to initial monotherapy, without any all-ranking purpose scheme. Revised therapeutic algorithm for achieving target BP. Revised attention to resistant hypertension. 2. DEFINITIONS AND CLASSIFICATIONS The continuous relationship between BP and cardiovascular and renal events make the distinction between normotension and hypertension difficult. In practice, however, cut-off BP values are universally used to facilitate the decision about treatment (Table 3).TABLE 3: Definitions and classification of office blood pressure levels (mmHg)In order to help prognosis, total cardiovascular risk should be stratified in different categories (low, moderate, high and very high risk referred to the 10-year risk of cardiovascular mortality), based on BP category, cardiovascular risk factors, asymptomatic organ damage and presence of diabetes, and symptomatic cardiovascular disease or chronic kidney disease (CKD), as summarized in Fig. 1.FIGURE 1: Stratification of total cardiovascular risk in categories of low, moderate, high and very high risk according to SBP and DBP and presence of risk factors (RFs), asymptomatic organ damage (OD), diabetes, chronic kidney disease (CKD) stage or symptomatic cardiovascular disease (CVD). Individuals with a high normal office but a raised out-of-office BP (masked hypertension) have a cardiovascular risk in the hypertension range. Individuals with a high office BP but normal out-of-office BP (white-coat hypertension), particularly if there is no diabetes, OD, CVD or CKD, have lower risk than sustained hypertension for the same office BP. BP, blood pressure; CV, cardiovascular; DBP, diastolic blood pressure; HT, hypertension; SBP, systolic blood pressure.3. DIAGNOSTIC EVALUATION The initial evaluation of a patient with hypertension should confirm the diagnosis of hypertension; detect causes of secondary hypertension; and assess cardiovascular risk, organ damage and concomitant clinical conditions. This calls for BP measurement, medical history including family history, physical examination, laboratory investigation and further diagnostic tests. Some of the investigations are needed in all patients; others only in specific patient groups. 3.1 Blood pressure measurement 3.1.1 Office and out-of-office blood pressure Although conventional office BP measurement currently remains the ‘gold standard’ for screening, diagnosis and management of hypertension, it is generally accepted that out-of-office BP provides important adjunct information. At present, BP can no longer be estimated using a mercury manometer in many – although not all – European countries. Auscultatory or oscillometric semiautomatic sphygmomanometers are used instead, but these devices should be validated according to standardized protocols and their accuracy checked periodically. Table 4 gives instructions for correct office BP measurements, and Table 5 provides clinical indications for out-of-office BP measurement, namely measurements at home or over the 24 h.TABLE 4: Office blood pressure measurementTABLE 5: Clinical indications for out-of-office blood pressure measurement for diagnostic purposesOffice BP is usually higher than ambulatory and home BP and the difference increases as office BP increases. Cut-off values for the definition of hypertension by home and ambulatory BP are reported in Table 6.TABLE 6: Definitions of hypertension by office and out-of-office blood pressure levels3.1.2 White-coat and masked hypertension The term ‘white-coat’ or ‘isolated office’ hypertension refers to a condition in which BP is elevated in the office at repeated visits and normal out of the office either on ambulatory blood pressure monitoring or on home blood pressure monitoring. Conversely, BP may be normal in the office and abnormally high out of the medical environment, which is termed ‘masked’ or ‘isolated ambulatory’ hypertension. Cut-off values to be used are those in Table 6. 3.1.3 Central blood pressure Owing to the variable superposition of incoming and reflected pressure waves along the arterial tree, aortic BP (central BP) may be different from brachial BP. Central BP can be estimated indirectly by various methods. The current guidelines consider that, despite the growing interest in these methods, more investigation is needed before recommending the routine measurement of central BP for clinical use. 3.2 Medical history The information to be obtained at the time of the first diagnosis of hypertension is indicated in Table 7.TABLE 7: Personal and family medical history3.3 Physical examination Physical examination aims to establish or verify the diagnosis of hypertension, establish current BP, screen for secondary causes of hypertension and refine global cardiovascular risk. Procedures for BP measurement are indicated in Tables 4 and 5. Other information to be obtained by physical examination is in Table 8.TABLE 8: Physical examination for secondary hypertension, organ damage and obesity3.4 Laboratory investigations Laboratory investigations are directed at providing evidence for additional risk factors, searching for secondary hypertension and looking for organ damage. Investigations should proceed from the most simple to the more complicated ones, as summarized in Table 9.TABLE 9: Laboratory investigations3.5 Searching for asymptomatic organ damage Owing to the importance of asymptomatic organ damage as an intermediate stage in the continuum of cardiovascular disease, and as a determinant of overall cardiovascular disease, signs of organ involvement should be sought carefully by appropriate techniques as indicated below.Figure3.6 Searching for secondary forms of hypertension A specific, potentially reversible cause of BP elevation can be identified in a relatively small number of adult patients with hypertension. However if basal work-up leads to the suspicion of a secondary form of hypertension, the patient should be referred to a specialized centre where specific diagnostic procedures may be performed. 4. TREATMENT APPROACH 4.1 Recommendations of previous guidelines revised The 2007 ESH/ESC Guidelines, like many other scientific guidelines, recommended the use of antihypertensive drugs in patients with Grade 1 hypertension even in the absence of other risk factors or organ damage after nonpharmacological treatment had proved unsuccessful. This recommendation also specifically included the elderly hypertensive patient. The 2007 Guidelines also suggested drug treatment of patients with diabetes, previous cardiovascular disease (CVD) or CKD even when their BP was in the high normal range (130–139/85–89 mmHg). Furthermore, a lower BP target was recommended for these high or very high risk patients (<130/80 mmHg) than in patients at low–moderate risk (<140/90 mmHg). These recommendations were reappraised in a 2009 ESH Task Force document on the basis of an extensive critical review of the evidence. The following now summarizes the conclusions for the current guidelines: attention should be directed to the Class of recommendation and the Level of evidence, in order to distinguish what is considered compelling and what simply prudent. Figure 2 also summarizes recommendations and suggestions for treatment initiation and BP targets in the context of total risk stratification of hypertensive individuals.FIGURE 2: Initiation of lifestyle changes and antihypertensive drug treatment. Targets of treatment are also indicated. Colours are as in Fig. 1. See 4.3 and 6.5 for evidence that, in patients with diabetes, the optimal DBP target is between 80 and 85 mmHg. In the high normal blood pressure (BP) range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). See 4.2 and 6.3 for lack of evidence in favour of drug treatment in young individuals with isolated systolic hypertension. CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; HT, hypertension; OD, organ damage; RF, risk factor; SBP, systolic blood pressure.4.2 When to initiate antihypertensive drug treatmentFigure4.3 Blood pressure treatment targetsFigure5. TREATMENT STRATEGIES 5.1 Lifestyle changes Appropriate lifestyle changes are the cornerstone for the prevention of hypertension. They are also important for its treatment, although they should never delay the initiation of drug therapy in patients at high level of risk. In addition to the BP-lowering effect, lifestyle changes contribute to the control of other cardiovascular risk factors and clinical conditions. The lifestyle measures that have been shown to be capable of reducing BP and therefore recommended are as follows: salt restriction to 5–6 g/day; moderation of alcohol consumption to no more than 20–30 g of ethanol per day in men and 10–20 g/day in women; high consumption of vegetables and fruits and low-fat dairy products; reduction of weight to a BMI of 25 kg/m2 and waist circumference to less than 102 cm in men and less than 88 cm in women; at least 30 min of moderate dynamic exercise on 5 to 7 days per week. 5.2 Pharmacological therapy 5.2.1 Choice of antihypertensive drugs The current guidelines reconfirm that all major classes of antihypertensive agents are suitable for the initiation and maintenance of antihypertensive treatment either in monotherapy or in some combinations, and that no all-purpose ranking of drugs for general antihypertensive usage is evidence based. All classes have their advantages but also contraindications, and may be preferentially used or avoided in specific conditions. Contraindications and preferred indications are listed in Tables 10 and 11.TABLE 10: Compelling and possible contraindications to the use of antihypertensive drugsTABLE 11: Drugs to be preferred in specific conditions5.2.2 Monotherapy and combination therapy The current guidelines share the 2007 Guidelines’ opinion that monotherapy can reduce BP to target only in a limited number of patients and that most patients require the combination of at least two drugs, and they reconfirm that initiation with a drug combination can be considered in patients at high cardiovascular risk or with markedly high BP. The algorithm of Fig. 3, however, is a modification of the 2007 one, to emphasize that adding drugs to drugs should be done with attention to results and any compound overtly ineffective or minimally effective should be replaced, rather than retained in an automatic step-up multiple-drug approach. Combinations to be preferred or avoided are illustrated in Fig. 4.FIGURE 3: Monotherapy vs. drug combination strategies to achieve target blood pressure (BP). CV, cardiovascular.FIGURE 4: Possible combinations of classes of antihypertensive drugs. Green continuous lines: preferred combinations; green dashed line: useful combination (with some limitations); black dashed lines: possible but less well tested combinations; red continuous line: not recommended combination. Although verapamil and diltiazem are sometimes used with a β-blocker to improve ventricular rate control in permanent atrial fibrillation, only dihydropyridine calcium antagonists should normally be combined with β-blockers. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. *Thiazide diuretics also include thiazide-like compounds (chlorthalidone) and indapamide.Strengths of recommendations about choice of drugs and combinations of antihypertensive agents are given in the summary table below.Figure6. TREATMENT STRATEGIES IN SPECIAL CONDITIONS Summary recommendations for antihypertensive treatment strategies in various conditions are listed below. 6.1 White-coat and masked hypertensionFigure6.2 ElderlyFigure6.3 Young adultsFigure6.4 WomenFigure6.5 Diabetes mellitusFigure6.6 Metabolic syndromeFigure6.7 Diabetic and nondiabetic nephropathyFigure6.8 Cerebrovascular diseaseFigure6.9 Heart diseaseFigure6.10 Atherosclerosis, arteriosclerosis and peripheral artery diseaseFigure6.11 Resistant hypertensionFigure7. TREATMENT OF ASSOCIATED RISK FACTORSFigure8. FOLLOW-UP 8.1 Follow-up visits After initiation of antihypertensive drug therapy, it is important to see the patient at 2-week to 4-week intervals to evaluate the effects on BP and to assess possible side-effects. Some medications will have an effect within days or weeks but a continued delayed response may occur during the first 2 months. Once the target is reached, a visit interval of a few months is reasonable. 8.2 Elevated blood pressure at control visits Patients and physicians have a tendency to interpret an uncontrolled BP at a given visit as due to occasional factors and thus to downplay its clinical significance. Due attention should be given to poor adherence or irregular consumption of drugs (sometimes because of adverse effects), to the white-coat effect and to substances or drugs opposing the antihypertensive effect of treatment. 8.3 Can antihypertensive medication be stopped? In some patients, in whom treatment is accompanied by an effective BP control for an extended period, it may be possible to reduce the number and dosage of drugs. This may be particularly the case if BP control is accompanied by healthy lifestyle changes. Reduction of medications should be made gradually and the patient should frequently be checked because of the risk of reappearance of hypertension. 9. IMPROVEMENT OF BLOOD PRESSURE CONTROL IN HYPERTENSION Despite overwhelming evidence that hypertension is a major cardiovascular risk factor and that BP-lowering substantially reduce the risk, there is evidence that all over the world a noticeable proportion of hypertensive individuals are unaware of this condition or, if aware, do not undergo treatment; target BP values are seldom achieved; failure to achieve BP control is associated with persistence of an elevated cardiovascular risk; and the rate of awareness of hypertension and BP control is improving slowly or not at all. As a consequence, high BP remains a leading cause of death and cardiovascular morbidity in Europe, as elsewhere in the world. Overall, three main causes of the low rate of BP control in real life have been identified: physician inertia; patient low adherence to treatment; and deficiencies of healthcare systems in their approach to chronic diseases. Methods to improve adherence to physicians’ recommendations are listed in Table 12.TABLE 12: Methods to improve adherence to physicians’ recommendations

In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance.

Expression of cDNA libraries from human melanoma, renal cancer, astrocytoma, and Hodgkin disease in Escherichia coli and screening for clones reactive with high-titer IgG antibodies in autologous patient serum lead to the discovery of at least four antigens with a restricted expression pattern in each tumor. Besides antigens known to elicit T-cell responses, such as MAGE-1 and tyrosinase, numerous additional antigens that were overexpressed or specifically expressed in tumors of the same type were identified. Sequence analyses suggest that many of these molecules, besides being the target of a specific immune response, might be of relevance for tumor growth. Antibodies to a given antigen were usually confined to patients with the same tumor type. The unexpected frequency of human tumor antigens, which can be readily defined at the molecular level by the serological analysis of autologous tumor cDNA expression cloning, indicates that human neoplasms elicit multiple specific immune responses in the autologous host and provides diagnostic and therapeutic approaches to human cancer.

BACKGROUND: Treatment of coronary in-stent restenosis is hampered by a high incidence of recurrent in-stent restenosis. We assessed the efficacy and safety of a paclitaxel-coated balloon in this setting. METHODS: We enrolled 52 patients with in-stent restenosis in a randomized, double-blind, multicenter trial to compare the effects of a balloon catheter coated with paclitaxel (3 microg per square millimeter of balloon surface area) with those of an uncoated balloon catheter in coronary angioplasty. The primary end point was late luminal loss as seen on angiography. Secondary end points included the rates of restenosis (a binary variable) and major adverse cardiac events. RESULTS: Multivessel disease was present in 80% of patients in both groups. Quantitative coronary angiography revealed no significant differences in baseline measures. At 6 months, angiography showed that the mean (+/-SD) in-segment late luminal loss was 0.74+/-0.86 mm in the uncoated-balloon group versus 0.03+/-0.48 mm in the coated-balloon group (P=0.002). A total of 10 of 23 patients (43%) in the uncoated-balloon group had restenosis, as compared with 1 of 22 patients (5%) in the coated-balloon group (P=0.002). At 12 months, the rate of major adverse cardiac events was 31% in the uncoated-balloon group and 4% in the coated-balloon group (P=0.01). This difference was primarily due to the need for target-lesion revascularization in six patients in the uncoated-balloon group (P=0.02). CONCLUSIONS: Treatment of coronary in-stent restenosis with paclitaxel-coated balloon catheters significantly reduced the incidence of restenosis. These data suggest that the inhibition of restenosis by local drug delivery may not require stent implantation and sustained drug release at the site of injury. (ClinicalTrials.gov number, NCT00106587 [ClinicalTrials.gov].).

The ESH/ESC Guidelines represent the views of the ESH and ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

Endothelial cell damage is one important pathophysiological step of atherosclerosis and restenosis after angioplasty. Accelerated reendothelialization impairs neointima formation. We evaluated the role of intravenously transfused endothelial progenitor cells (EPCs) on reendothelialization and neointima formation in a mouse model of arterial injury. Spleen-derived mouse mononuclear cells (MNCs) were cultured in endothelial basal medium. A total of 91.8+/-3.2% of adherent cells showed uptake of acetylated low-density lipoprotein (Dil-Ac-LDL) and lectin binding after 4 days. Immunostaining and long-term cultures confirmed the endothelial progenitor phenotype. To determine the effect of stem cell transfusion on reendothelialization, mice received either fluorescent-labeled spleen-derived MNCs or in vitro differentiated EPCs intravenously after endothelial injury of the carotid artery. Transfused cells were strictly restricted to the injury site, and lectin binding confirmed the endothelial phenotype. Homing of transfused cells to the site of injury was only detectable in splenectomized mice. Cell transfusion caused enhanced reendothelialization associated with a reduction of neointima formation. Systemically applied spleen-derived MNCs and EPCs home to the site of vascular injury, resulting in an enhanced reendothelialization associated with decreased neointima formation. These results allow novel insights in stem cell biology and provide additional information for the treatment of vascular dysfunction and prevention of restenosis after angioplasty. The full text of this article is available online at http://www.circresaha.org.

BACKGROUND: The objective of this study was to identify the prognostic indicators in patients with suspected myocarditis who underwent endomyocardial biopsy. METHODS AND RESULTS: Between 1994 and 2007, 181 consecutive patients (age, 42+/-15 years) with clinically suspected viral myocarditis were enrolled and followed up for a mean of 59+/-42 months. Endomyocardial biopsies were studied for inflammation with histological (Dallas) and immunohistological criteria. Virus genome was detected by polymerase chain reaction. The primary end point was time to cardiac death or heart transplantation. In 38% of the patients (n=69), the Dallas criteria were positive. Immunohistological signs of inflammation were shown in 50% (n=91). Genomes of cardiotropic virus species were detected in 79 patients (44%). During follow-up, 22% of the patients (n=40) reached the primary end point. Three independent predictors were identified for the primary end point, namely New York Heart Association class III or IV at entry (hazard ratio, 3.20; 95% confidence interval, 1.36 to 7.57; P=0.008), immunohistological evidence of inflammatory infiltrates in the myocardium (hazard ratio, 3.46; 95% confidence interval, 1.39 to 8.62; P=0.008), and beta-blocker therapy (hazard ratio, 0.43; 95% confidence interval, 0.21 to 0.91; P=0.027). Ejection fraction, left ventricular end-diastolic pressure, and left ventricular end-diastolic dimension index were predictive only in univariate, not in multivariate, analysis. Neither the Dallas criteria nor the detection of viral genome was a predictor of outcome. CONCLUSIONS: For patients with suspected myocarditis, advanced New York Heart Association functional class, immunohistological signs of inflammation, and lack of beta-blocker therapy, but not histology (positive Dallas criteria) or viral genome detection, are related to poor outcome.

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.

BACKGROUND: Hypertension is associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. We investigated the effect of catheter-based renal sympathetic denervation on glucose metabolism and blood pressure control in patients with resistant hypertension. METHODS AND RESULTS: We enrolled 50 patients with therapy-resistant hypertension. Thirty-seven patients underwent bilateral catheter-based renal denervation, and 13 patients were assigned to a control group. Systolic and diastolic blood pressures, fasting glucose, insulin, C peptide, hemoglobin A(1c), calculated insulin sensitivity (homeostasis model assessment-insulin resistance), and glucose levels during oral glucose tolerance test were measured before and 1 and 3 months after treatment. Mean office blood pressure at baseline was 178/96±3/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by -28/-10 mm Hg (P<0.001) and -32/-12 mm Hg (P<0.001), respectively, in the treatment group, without changes in concurrent antihypertensive treatment. Three months after renal denervation, fasting glucose was reduced from 118±3.4 to 108±3.8 mg/dL (P=0.039). Insulin levels were decreased from 20.8±3.0 to 9.3±2.5 μIU/mL (P=0.006) and C-peptide levels from 5.3±0.6 to 3.0±0.9 ng/mL (P=0.002). After 3 months, homeostasis model assessment-insulin resistance decreased from 6.0±0.9 to 2.4±0.8 (P=0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL (P=0.012). There were no significant changes in blood pressure or metabolic markers in the control group. CONCLUSIONS: Renal denervation improves glucose metabolism and insulin sensitivity in addition to a significantly reducing blood pressure. However, this improvement appeared to be unrelated to changes in drug treatment. This novel procedure may therefore provide protection in patients with resistant hypertension and metabolic disorders at high cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00664638 and NCT00888433.

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Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB. This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.