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Direct or new oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have recently revolutionized the field of antithrombotic therapy for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (NVAF). Randomized controlled trials have shown that these agents have at least comparable efficacy with vitamin K antagonists along with superior safety, at least in what concerns intracranial hemorrhage. As a result, NOACs are indicated as first-line anticoagulation therapy for NVAF patients with at least one risk factor for stroke or systemic embolism. The rapid introduction, however, of NOACs in a field dominated for decades by vitamin antagonists and the variety of agents and dosing schemes may create difficulties in decision making. In the present article, we attempt to determine a practical approach to the choice of agent and dose in different clinical scenarios by considering not only the results of seminal randomized trials and post hoc analyses but also data from real-world patient populations as well as the recently available possibility of rapid NOAC reversal., (© 2018 S. Karger AG, Basel.)

Backround: Left atrial (LA) enlargement plays an important role in the development of heart failure (HF) and is a robust prognostic factor. Fibrotic processes have also been advocated to evoke HF through finite signalling proteins., Methods: We examined the association of two such proteins, cystatin C (CysC) and galectin-3 (Gal-3), and other clinical, echocardiographic and biochemical parameters with LA volume index (LAVi) in patients with HF with severely impaired left ventricular ejection fraction (LVEF). Severe renal, liver, autoimmune disease and cancer were exclusion criteria., Results: A total of 40 patients with HF (31 men, age 66.6 ± 1.7) with LVEF = 25.4 ± 0.9% were divided into two groups according to the mean LAVi (51.03 ± 2.9 ml/m 2 ) calculated by two-dimensional transthoracic echocardiography. Greater LAVi was positively associated with LV end-diastolic volume ( p = 0.017), LV end-systolic volume ( p = 0.025), mitral regurgitant volume (MRV) ( p = 0.001), right ventricular systolic pressure (RVSP) ( p < 0.001), restrictive diastolic filling pattern ( p = 0.003) and atrial fibrillation ( p = 0.005). Plasma CysC was positively correlated with LAVi ( R 2 = 0.135, p = 0.019) and log-transformed plasma Gal-3 ( R 2 = 0.109, p = 0.042) by simple linear regression analysis. Stepwise multiple linear regression analysis showed that only MRV ( t = 2.236, p = 0.032), CysC ( t = 2.467, p = 0.019) and RVSP ( t = 2.155, p = 0.038) were significant predictors of LAVi., Conclusions: Apart from known determinants of LAVi, circulating CysC and Gal-3 were associated with greater LA dilatation in patients with HF with reduced LVEF. Interestingly, the correlation between these two fibrotic proteins was positive.

β-Thalassemia minor (β-Τm) is associated with rheological and biochemical alterations that can affect cardiovascular function. We aimed to evaluate the elastic arterial properties and the pulse wave augmentation indices in a population of patients with β-Τm. Seventy-five individuals with β-Τm (age 55.5 [42.75-65.25], women 48%) and 127 controls (age 57 years [48-63], women 55.1%) underwent comprehensive echocardiographic evaluation and applanation tonometry of the radial and femoral artery. Pulse wave analysis revealed that augmentation pressure, augmentation index (AIx), and heart rate-corrected AIx were significantly lower (median [interquartile range]: 8.75 [4.625-13] vs 11 [6.5-14.5], P = .017; 26.5 [17.5-33.375] vs 30.5 [20.75-37.5], P = .014; and 22.25 [15.125-29.5] vs 27 [20.5-33], P = .008, respectively) in the β-Τm group compared to controls. The left atrial active emptying volume was significantly lower and the isovolumic relaxation time was shorter in the β-Τm group compared to the control group (10.2 [7.4-14.4] vs 12.0 [8.6-15.8], P = .040 and 78 [70-90] vs 90 [70-104], P = .034, respectively). β-Thalassemia minor is associated with favorable pulse wave augmentation indices and left ventricular diastolic function profile in asymptomatic individuals with cardiovascular risk factors.

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Red blood cell distribution width (RDW) is an established prognostic marker in acute and chronic heart failure (HF). Recent studies have pointed out a link among RDW, diabetes mellitus (DM) and inflammation. We sought to investigate the prognostic value and longitudinal pattern of RDW in patients with concomitant HF and DM, which remains unknown., Methods: A total of 218 patients (71 diabetics) who presented with acute HF had RDW measured at admission, discharge and 4, 8 and 12 months post-discharge. The study endpoint was all-cause mortality or rehospitalization for HF during 1-year follow-up., Results: The study endpoint was met in 33 patients (46.5%) with DM and in 54 patients (36.7%) without DM. RDW at admission was associated with higher event rate both in HF patients with and without DM (adjusted HR: 1.349, p = 0.002, 95% CI 1.120-1.624 and adjusted HR: 1.142, p = 0.033, 95% CI 1.011-1.291 respectively). In addition, a significant interaction was found between diabetes and RDW longitudinal changes (β interaction  = -0.002; SE = 0.001; p = 0.042)., Conclusions: Despite the similar prognostic significance of RDW in diabetic and non-diabetic HF patients regarding the study endpoint, longitudinal changes were found to be significantly different between these two groups of HF patients. This might be due to the higher inflammatory burden that diabetic HF patients carry and may provide new insights to the pathophysiological mechanism of RDW increase in HF, which remains unknown.

Objective: To determine the association between copayment, medication adherence and outcomes in patients with Heart failure (HF) and Diabetes Mellitus (DM)., Methods: PubMed, Scopus and Cochrane databases were searched using combinations of four sets of key words for: drug cost sharing; resource use, health and economic outcomes; medication adherence; and chronic disease., Results: Thirty eight studies were included in the review. Concerning the direct effect of copayment changes on outcomes, the scarcity and diversity of data, does not allow us to reach a clear conclusion, although there is some evidence indicating that higher copayments may result in poorer health and economic outcomes. Seven and one studies evaluating the relationship between copayment and medication adherence in DM and HF population, respectively, demonstrated an inverse statistically significant association. All studies (29) examining the relationship between medication adherence and outcomes, revealed that increased adherence is associated with health benefits in both DM and HF patients. Finally, the majority of studies in both populations, showed that medication adherence was related to lower resource utilization which in turn may lead to lower total healthcare cost., Conclusion: The results of our systematic review imply that lower copayments may result in higher medication adherence, which in turn may lead to better health outcomes and lower total healthcare expenses. Future studies are recommended to reinforce these findings., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fibrillation (AF) and to convert it into sinus rhythm. However, due to its delayed onset of action, ranolazine (RAN), a new antianginal agent with atrial-selective electrophysiologic properties, has recently been attempted as add-on therapy with AMIO to facilitate AF conversion., Methods: To establish the role of this combination therapy, we enrolled 173 consecutive patients (68 ± 10 years, 54% male) with recent-onset (<48-hour duration) AF who were eligible for pharmacologic cardioversion. Patients were randomized to intravenous AMIO (loading dose 5 mg/kg in 1 hour followed by 50 mg/h; n = 81), or AMIO plus a single oral dose of RAN 1 g (n = 92)., Results: Mean left atrial diameter did not significantly differ between groups, AMIO and AMIO + RAN (4.2 ± 0.5 cm vs 4.1 ± 0.4 cm, P = 0.18). The AMIO + RAN group compared with the AMIO-only group showed significantly shorter time to conversion (8.6 ± 2.8 hours vs 19.4 ± 4.4 hours, P < 0.0001) and higher conversion rate at 24 hours (98% vs 58%, P < 0.001). Left ventricular ejection fraction did not markedly vary between the two groups and ranged within moderately reduced values. No serious clinically evident adverse effects were observed in any of the patients receiving either AMIO or the combination treatment., Conclusions: Our data demonstrate faster sinus rhythm restoration and enhanced conversion rate of AF after AMIO plus RAN in patients with preserved ejection fraction and left atrial size, implicating a synergistic effect of the two agents., (© 2017 Wiley Periodicals, Inc.)

Heart failure is a common clinical syndrome associated with significant morbidity and mortality worldwide. Ischemic heart disease is the leading cause of heart failure, at least in the industrialized countries. Proper diagnosis of the syndrome and management of patients with heart failure require anatomical and functional information obtained through various imaging modalities. Nuclear cardiology techniques play a main role in the evaluation of heart failure. Myocardial single photon emission computed tomography (SPECT) with thallium-201 or technetium-99 m labelled tracers offer valuable data regarding ventricular function, myocardial perfusion, viability, and intraventricular synchronism. Moreover, positron emission tomography (PET) permits accurate evaluation of myocardial perfusion, metabolism, and viability, providing high-quality images and the ability of quantitative analysis. As these imaging techniques assess different parameters of cardiac structure and function, variations of sensitivity and specificity have been reported among them. In addition, the role of SPECT and PET guided therapy remains controversial. In this comprehensive review, we address these controversies and report the advances in patient's investigation with SPECT and PET in ischemic heart failure. Furthermore, we present the innovations in technology that are expected to strengthen the role of nuclear cardiology modalities in the investigation of heart failure.

The left atrium plays an important role in the maintenance of cardiovascular and neurohumoral homeostasis in heart failure. However, with progressive left ventricular dysfunction, left atrial (LA) dilation and mechanical failure develop, which frequently culminate in atrial fibrillation. Moreover, LA mechanical failure is accompanied by LA endocrine failure [deficient atrial natriuretic peptide (ANP) processing-synthesis/development of ANP resistance) and LA regulatory failure (dominance of sympathetic nervous system excitatory mechanisms, excessive vasopressin release) contributing to neurohumoral overactivity, vasoconstriction, and volume overload (global LA failure). The purpose of the present review is to describe the characteristics and emphasize the clinical significance of global LA failure in patients with heart failure., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background/objectives: Cystatin-C and beta-2-microglobulin may be superior to serum creatinine, blood urea nitrogen (BUN), or estimated glomerular filtration rate (eGFR) in patients hospitalized with heart failure (HF). We compared these renal markers in ambulatory HF patients., Methods: We prospectively evaluated the association of baseline renal markers and eGFR (by 4 different formulas) with (1) the composite of death or HF-related hospitalization and (2) rates of hospitalizations and emergency department (ED) visits in 166 outpatients with HF (57.3±11.6years; 57.2% white, 38.6% black, median left ventricular ejection fraction 27.5% [17.5, 40.0])., Results: After a median of 3.9years, 63 (38.0%) patients met the composite endpoint. There were 458 hospitalizations (177 [38.6%] for HF) and 209 ED visits (51 [24.4%] for HF). Cystatin-based eGFR most consistently predicted (1) the composite endpoint (highest-to-lowest tertile adjusted hazard ratio [HR] 4.92 [95% CI 2.07-11.7; P<0.001]); and (2) hospitalization rates, including HF hospitalizations (highest-to-lowest tertile, adjusted relative rate 5.24 [95% CI 1.61-17.01; P=0.006]). Serum creatinine alone was a strong predictor of the composite endpoint (highest-to-lowest tertile, adjusted HR 3.20 [95% CI, 1.51-6.78; P=0.002]). Only the highest tertile of BUN was associated with rates of ED visits., Conclusions: In outpatients with HF, cystatin-based eGFR provides consistent prognostication across outcomes, except ED visits. Serum creatinine is an adequate prognosticator of death or HF hospitalization., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Several co-existing diseases and/or conditions (co-morbidities) are present in patients with heart failure (HF), with diverse clinical relevance. Multiple mechanisms may underlie the co-existence of HF and co-morbidities, including direct causation, associated risk factors, heterogeneity, and independence. The complex inter-relationship of co-morbidities and their impact on the cardiovascular system contribute to the features of HF, both with reduced (HFrEF) and preserved ejection fraction (HFpEF). The purpose of this work is to provide an overview of the contribution of major cardiac and non-cardiac co-morbidities to HF development and outcomes, in the context of both HFpEF and HFrEF. Accordingly, epidemiological evidence linking co-morbidities to HF and the effect of prevalent and incident co-morbidities on HF outcome will be reviewed., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aim: Neutrophil gelatinase-associated lipocalin (NGAL) and ST2 receptor, a member of the interleukin-1 receptor family, are novel biomarkers with a potential role in the diagnosis and risk stratification of patients with chronic heart failure (CHF). There is however scarce data on their relation with clinical characteristics and cardiac function in patients with CHF., Methods: Consecutive ambulatory patients with CHF were studied. All patients underwent clinical and echocardiographic assessment, and blood samples were collected for the estimation of ST2 and NGAL serum levels during the same assessment., Results: A total of 76 patients (79% male, mean age: 63 ± 14 years), with CHF and left ventricular ejection fraction of 28 ± 7% were included. Median NGAL was 0.16 (0.09-0.275) mg/L and median ST2 was 0.0125 (0.0071-0.0176) mg/L. No association between NGAL and ST2 was observed. Multivariate analysis revealed tissue Doppler-derived right ventricular systolic velocity as an independent predictor of ST2, and the duration of HF and serum creatinine levels as independent predictors of NGAL., Conclusions: NGAL levels depend on the renal function and the duration of HF, while ST2 levels are affected by the right but not the left ventricular function and show no association with clinical indices of HF.

Introduction: In this study we evaluated factors that affect the early and long-term postoperative outcomes of patients with infective endocarditis., Methods: We retrospectively reviewed 94 patients (68 male, 26 female, mean age 58.3 ± 13.1 years, range 20-85 years) with proven infective native (n=85) or prosthetic valve (n=9) endocarditis who underwent heart valve surgery between September 1997 and December 2007. Fifty-four patients (57.4%) underwent aortic, 28 (29.8%) mitral, 3 (3.2%) tricuspid, 8 (8.5%) double, and one patient (1%) triple valve surgery. In 75.5% of the procedures we implanted mechanical valves, in 13.8% biological prostheses, and 10.7% were reconstructive or other procedures. Midterm follow up was 100% complete with a cumulative duration of 545 patient-years (maximum 12 years)., Results: Overall hospital mortality (30 days) was 8.5% (n=8). Causes of early mortality were low cardiac output syndrome in 2 cases, sepsis with multiple organ failure in 5 cases, and intracerebral bleeding in one patient. Development of postoperative low cardiac output syndrome (p=0.01) was identified as an independent predictor of early mortality. Overall late mortality was 25.6% (n=22) with a cumulative rate of 4.03% per patient-year. Causes of late death were predominantly of extracardiac origin. Kaplan-Meier survival analysis revealed a cumulative survival rate at 12 years of 57.2%. Cox regression analysis identified diabetes mellitus (p=0.016) and postoperative low cardiac output syndrome (p=0.03) as independent late mortality factors., Conclusions: Heart valve surgery in patients with infective endocarditis is associated with increased but acceptable early and long-term mortality. The mid-term prognosis is similar to that of patients undergoing elective valve replacement surgery.

Identification of genetic predisposition to cardiac sarcoidosis could play a critical role in the detection of sub-clinical forms of the disease. The aim of this study was to investigate the possible correlations between the emergence of cardiac sarcoidosis and the -1.031T/C, -857C/T, -308G/A, and -238G/A Tumor Necrosis Factor-α (TNFA) polymorphisms in a well-defined Greek cohort. One-hundred and seventy-three patients of Greek origin with sarcoidosis were recruited in the present study. Cardiac sarcoidosis was determined according to established criteria. Blood samples were collected and the TNFA polymorphisms were genotyped. No significant difference was noted between the patients with cardiac involvement and those without, concerning the -1.031T/C and -238G/A TNFA polymorphisms. Regarding the -857C/T polymorphism, the TT genotype and the T allele were found to be over-represented in patients with cardiac involvement (p=0.02 and 0.012, respectively). AA genotype of the -308G/A as well as the A allele were also found significantly more frequently in patients with cardiac sarcoidosis (p=0.014 and 0.012 respectively). From the investigated TNFA promoter polymorphisms, we were able to deduce nine main haplotypes. Haplotypes 3 and 5, including A nucleotide at position -308, and T nucleotide at position -857 respectively, were significantly over-represented in the group with cardiac involvement. We detected an increased presence of genetic polymorphisms in the TNFA gene of patients with cardiac involvement. However, the role and the clinical application of these findings need further exploration., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Atrial fibrillation (AF) is common in patients with systemic sclerosis (SSc) and is associated with significant morbidity, mortality, and healthcare expenditures. The aim of this study was to prospectively determine the incidence and the independent predictors of AF in this patient population., Methods: Forty-nine patients (age 50.15 ± 9.25 years, 87.8% female) and 21 healthy controls, all in sinus rhythm, were studied. Evaluation included blood sampling, B-type natriuretic peptide (BNP) measurement, comprehensive electrocardiography and echocardiography at baseline, and 24h ambulatory Holter monitoring at baseline and every 6 months., Results: During a mean follow-up of 72 ± 24 months, 18 SSc patients (36.7%) developed AF (SSc-AF group) while 31 remained in sinus rhythm (SSc-SR group); all subjects in the control group (Cl group) remained in SR. Baseline differences between SSc-AF, SSc-SR, and Cl groups included: a) left ventricular (LV) mass: 84.5 ± 26 vs. 71.8 ± 18.6 vs. 60.5 ± 32.6 g/m(2), respectively (p=0.017); b) mitral tissue Doppler imaging E velocity: 14.5 ± 2.8 vs. 17.5 ± 3.4 vs. 20.5 ± 4.4 cm/s (p<0.001); c) left atrial (LA) volume: 18.8 ± 7.8 vs. 13.5 ± 5.1 vs. 9.7 ± 5.4 cm(3)/m(2) (p<0.001); d) LA active emptying volume: 7.6 ± 2.7 vs. 4.7 ± 3.2 vs. 3.3 ± 2.2 cm(3)/m(2) (p<0.001); and e) logBNP: 1.78 ± 0.47 vs. 1.31 ± 0.54 vs. 0.66 ± 0.38 pg/mL (p<0.001). In Cox proportional hazard analysis, BNP was the only independent predictor of incident AF., Conclusion: Incident AF was high in SSc, especially in the presence of LV diastolic dysfunction with LA mechanical overload and elevated BNP levels. BNP was the only independent predictor of incident AF; therefore, it should be considered for risk stratification in this population.

It is well established that exercise induces excessive production of reactive species leading to oxidative stress, which has been implicated in oxidative damage of macromolecules, immune dysfunction, muscle damage and fatigue. The present study examined the effect of supplementation of ultra-marathon runners for a two-months-period with a special whey protein bar containing carbohydrates and protein in a specific ratio (1:1) (N=16), prepared using as starting material the by-products of cheese manufacturing, and supplementation with commercially available tomato juice (N=15). Thiobarbituric-acid reactive substances and protein carbonyls were significantly decreased in both supplementation groups, while a pronounced increased in reduced glutathione was observed in the protein bar group. Total anti-oxidant activity remained unchanged in both groups. Flow-mediated dilatation, used as an estimate of endothelial function, was increased in both groups, with a significant rise observed only in the tomato juice administration group. In conclusion, supplementation of ultra marathon runners for a two-months-period with a special protein bar and tomato juice significantly improved the oxidative status of the subjects, while tomato juice also improved vascular endothelial function in these athletes., (Copyright © 2014. Published by Elsevier Ltd.)

Aims: The role of low-dose dopamine infusion in patients with acute decompensated heart failure (ADHF) remains controversial. We aim to evaluate the efficacy and safety of high- versus low-dose furosemide with or without low-dose dopamine infusion in this patient population., Methods and Results: 161 ADHF patients (78 years; 46% female; ejection fraction 31%) were randomized to 8-hour continuous infusions of: a) high-dose furosemide (HDF, n=50, 20mg/h), b) low-dose furosemide and low-dose dopamine (LDFD, n=56, 5mg/h and 5 μg kg(-1)min(-1) respectively), or c) low-dose furosemide (LDF, n=55, furosemide 5mg/h). The main outcomes were 60-day and one-year all-cause mortality (ACM) and hospitalization for HF (HHF). Dyspnea relief (Borg index), worsening renal function (WRF, rise in serum creatinine (sCr) ≥ 0.3mg/dL), and length of stay (LOS) were also assessed. The urinary output at 2, 4, 6, 8, and 24h was not significantly different in the three groups. Neither the ACM at day 60 (4.0%, 7.1%, and 7.2%; P=0.74) or at one year (38.1%, 33.9% and 32.7%, P=0.84) nor the HHF at day 60 (22.0%, 21.4%, and 14.5%, P=0.55) or one year (60.0%, 50.0%, and 47%, P=0.40) differed between HDF, LDFD, and LDF groups, respectively. No differences in the Borg index or LOS were noted. WRF was higher in the HDF than in LDFD and LDF groups at day 1 (24% vs. 11% vs. 7%, P<0.0001) but not at sCr peak (44% vs. 38% vs. 29%, P=0.27). No significant differences in adverse events were noted., Conclusions: In ADHF patients, there were no significant differences in the in-hospital and post-discharge outcomes between high- vs. low-dose furosemide infusion; the addition of low-dose dopamine infusion was not associated with any beneficial effects., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Renal dysfunction (RD) is a frequent comorbid condition and a major determinant of outcomes in patients with heart failure (HF). It is likely that the etiology of RD in patients with HF is much more complex than we first thought and represents a matrix of independent, albeit interacting, pathophysiological pathways with effects on both the kidney and the heart that share a common denominator: aging and inflammation. Renal dysfunction in HF has been attributed, among others, to biochemical, hormonal, and hemodynamic factors, coupled with pharmacological interventions. Regardless of the cause, the development of RD or worsening renal function is common in patients with HF, and is associated with increased morbidity and mortality. There is increasing evidence, however, that transient increases in creatinine in the setting of acute HF are not prognostically important, whereas persistent deterioration does portend a higher mortality in this patient population. In addition, congestion seems to play an important role in the course of renal deterioration, and the combination of congestion and worsening renal function is the most significant clinical prognosticator in HF patients. This review aims to provide an update on the epidemiology and prognostic significance of RD in HF patients, in both the acute and the chronic setting.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide and, despite recent advances in therapy HF hospitalization rates remains unacceptably high. Prompt identification and optimal management of HF can affect long-term outcome. A valuable tool with diagnostic, prognostic, and treatment-guiding properties in this respect will be very useful, as exemplified by natriuretic peptides. However, natriuretic peptide levels show biological variation and are dependent on age, renal function, and body mass index. Recent advances in the field of molecular biology and HF pathophysiology have led to the discovery of other novel biomarkers that may have advantages. Among others, Galectin-3 (GAL3) and sST2 are 2 promising biomarkers that have been recently developed and can be used alone or in combination with natriuretic peptides in clinical practice. In the current paper, we review the existing data regarding GAL3 and sST2 in HF.

The relationship between echocardiographically measured epicardial fat thickness (EFT) and plasma concentrations of leptin, ghrelin, and adiponectin has not been evaluated in patients with noncachectic heart failure (HF). Patients with noncachectic HF and age- and sex-matched controls did not differ significantly in EFT, whereas EFT values showed significant positive correlation with body mass index (BMI) in both groups and were negatively related with brain natriuretic peptide and positively with log leptin values in the HF group. In the control group, a positive correlation with high-sensitivity C-reactive protein (hsCRP) and a negative correlation with log ghrelin were found. In multivariable analysis, log leptin was a significant predictor of EFT in patients with HF, but this effect was not retained after adjusting for BMI. In contrast, log ghrelin and hsCRP were significant predictors of EFT in controls even after adjusting for BMI.

Simultaneous adherence with multiple self-care instructions among heart failure (HF) patients is not well described. Patient-reported adherence to 8 recommendations related to exercise, alcohol, medications, smoking, diet, weight, and symptoms was assessed among 308 HF patients using the Medical Outcomes Study Specific Adherence Scale questionnaire (0="never" to 5="always," maximum score=40). A baseline cumulative score of ≥32/40 (average ≥80%) defined good adherence. Clinical events (death/transplantation/ventricular assist device), resource utilization, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were compared among patients with and without good adherence. The mean follow-up was 2.0±1.0 years, and adherence ranged from 26.3% (exercise) to 89.9% (medications). A cumulative score indicating good adherence was reported by 35.7%, whereas good adherence with every behavior was reported by 9.1% of patients. Good adherence was associated with fewer hospitalizations (all-cause 87.8 vs 107.6; P=.018; HF 29.6 vs 43.8; P=.007) and hospitalized days (all-cause 422 vs 465; P=.015; HF 228 vs 282; P<.001) per 100-person-years and better health status (KCCQ overall score 70.1±24.6 vs 63.8±22.8; P=.011). Adherence was not associated with clinical events or functional capacity. Patient-reported adherence with HF self-care recommendations is alarmingly low and selective. Good adherence was associated with lower resource utilization and better health status., (© 2012 Wiley Periodicals, Inc.)

Renal dysfunction is a common, important comorbidity in patients with both chronic and acute heart failure (HF). Chronic kidney disease and worsening renal function (WRF) are associated with worse outcomes, but our understanding of the complex bidirectional interactions between the heart and kidney remains poor. When addressing these interactions, one must consider the impact of intrinsic renal disease resulting from medical comorbidities on HF outcomes. WRF may result from any number of important processes. Understanding the role of each of these factors and their interplay are essential in understanding how to improve outcomes in patients with renal dysfunction and HF., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Diabetic cardiovascular autonomic neuropathy (DCAN), the impairment of the autonomic balance of the cardiovascular system in the setting of diabetes mellitus (DM), is frequently observed in both Type 1 and 2 DM, has detrimental effects on the quality of life and portends increased mortality. Clinical manifestations include: resting heart rate disorders, exercise intolerance, intraoperative cardiovascular lability, orthostatic alterations in heart rate and blood pressure, QT-interval prolongation, abnormal diurnal and nocturnal blood pressure variation, silent myocardial ischemia and diabetic cardiomyopathy. Clinical tests for autonomic nervous system evaluation, heart rate variability analysis, autonomic innervation imaging techniques, microneurography and baroreflex analysis are the main diagnostic tools for DCAN detection. Aldose reductase inhibitors and antioxidants may be helpful in DCAN therapy, but a regular, more generalized and multifactorial approach should be adopted with inclusion of lifestyle modifications, strict glycemic control and treatment of concomitant traditional cardiovascular risk factors, in order to achieve the best therapeutic results. In the present review, the authors provide aspects of DCAN pathophysiology, clinical presentation, diagnosis and an algorithm regarding the evaluation and management of DCAN in DM patients.

There has been increasing interest on the so-called cardiorenal syndrome (CRS), defined as a complex pathophysiological disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other. In this review, we contend that there is lack of evidence warranting the adoption of a specific clinical construct such as the CRS within the heart failure (HF) syndrome by demonstrating that: (a) the approaches and tools regarding the definition of kidney involvement in HF are suboptimal; (b) development of renal failure in HF is often confounded by age, hypertension, and diabetes; (c) worsening of renal function (WRF) in HF may be largely independent of alterations in cardiac function; (d) the bidirectional association between HF and renal failure is not unique and represents one of the several such associations encountered in HF; and (e) inflammation is a common denominator for HF and associated noncardiac morbidities. Based on these arguments, we believe that dissecting one of the multiple bidirectional associations in HF and constructing the so-called cardiorenal syndrome is not justified pathophysiologically. Fully understanding of all morbid associations and not only the cardiorenal is of great significance for the clinician who is caring for the patient with HF.

Cognitive impairment (CI) is increasingly recognized as a common adverse consequence of heart failure (HF). Although the exact mechanisms remain unclear, microembolism, chronic or intermittent cerebral hypoperfusion, and/or impaired cerebral vessel reactivity that lead to cerebral hypoxia and ischemic brain damage seem to underlie the development of CI in HF. Cognitive decline in HF is characterized by deficits in one or more cognition domains, including attention, memory, executive function, and psychomotor speed. These deficits may affect patients' decision-making capacity and interfere with their ability to comply with treatment requirements, recognize and self-manage disease worsening symptoms. CI may have fluctuations in severity over time, improve with effective HF treatment or progress to dementia. CI is independently associated with disability, mortality, and decreased quality of life of HF patients. It is essential therefore for health professionals in their routine evaluations of HF patients to become familiar with assessment of cognitive performance using standardized screening instruments. Future studies should focus on elucidating the mechanisms that underlie CI in HF and establishing preventive strategies and treatment approaches.

It has been widely suggested that depression negatively affects patients with cardiovascular disease. There are several pathophysiological mechanisms as well as behavioral processes linking depression and cardiac events. Improvements in nursing and medical care have prolonged survival of this patient population; however, this beneficial outcome has led to increased prevalence of depression. Since mortality rates in chronic heart failure patients remain extremely high, it might be as equally important to screen for depression and there are several valid and reliable screening tools that healthcare personnel could easily employ to identify patients at greater risk. Consultation should be provided by a multidisciplinary team, consisting of cardiologists, psychiatrists, and hospital or community nurses so as to carefully plan, execute, and evaluate medical intervention and implement lifestyle changes. We aim to systematically review the existing knowledge regarding current definitions, prognostic implications, pathophysiological mechanisms, and current and future treatment options in patients with depression and cardiovascular disease, specifically those with heart failure.

Heart failure (HF) is a growing epidemic with the annual number of hospitalizations constantly increasing over the last decades for HF as a primary or secondary diagnosis. Despite the emergence of novel therapeutic approached that can prolong life and shorten hospital stay, HF patients will be needing rehospitalization and will often have a poor prognosis. Telemonitoring is a novel diagnostic modality that has been suggested to be beneficial for HF patients. Telemonitoring is viewed as a means of recording physiological data, such as body weight, heart rate, arterial blood pressure, and electrocardiogram recordings, by portable devices and transmitting these data remotely (via a telephone line, a mobile phone or a computer) to a server where they can be stored, reviewed and analyzed by the research team. In this systematic review of all randomized clinical trials evaluating telemonitoring in chronic HF, we aim to assess whether telemonitoring provides any substantial benefit in this patient population.

Heart failure is a major public health problem and its management requires a significant amount of health care resources. Even with administration of the best available medical treatment, the mortality associated with the disease remains high. As therapeutical strategies for heart failure have been refined, the number of patients suffering from the disease has expanded dramatically. Although heart transplantation still represents the gold standard therapeutical approach, the implantation of mechanical circulatory support devices (MCSDs) evolved to a well-established management for this disease. The limited applicability of heart transplantation caused by a shortage of donor organs and the concurrent expand of the patient population with end-stage heart failure led to a considerable utilization of MCSDs. This paper outlines the current status of mechanical circulatory support.

Background: Clinical and experimental data suggest an association between the presence of bacterial and/or fungal infection and the development of different types of cancer, independently of chemotherapy-induced leukopenia. This has also been postulated for the development of lung cancer, however the prevalence and the exact species of the bacteria and fungi implicated, have not yet been described., Aim: To determine the presence of bacterial and fungal microflora in surgically extracted samples of patients with lung cancer., Materials and Methods: In this single-center prospective, observational study, tissue samples were surgically extracted from 32 consecutive patients with lung cancer, and reverse-transcription polymerase chain reaction (RT-PCR) was used to identify the presence of bacteria and fungi strains., Results: The analysis of the electrophoresis data pointed out diversity between the samples and the strains that were identified. Mycoplasma strains were identified in all samples. Strains that appeared more often were Staphylococcus epidermidis, Streptococcus mitis and Bacillus strains, followed in descending frequency by Chlamydia, Candida, Listeria, and Haemophilus influenza. In individual patients Legionella pneumophila and Candida tropicalis were detected., Conclusions: A diversity of pathogens could be identified in surgically extracted tissue samples of patients with lung cancer, with mycoplasma strains being present in all samples. These results point to an etiologic role for chronic infection in lung carcinogenesis. Confirmation of these observations and additional studies are needed to further characterize the etiologic role of inflammation in lung carcinogenesis.

Despite recent advances with neurohormonal antagonists and devices, the prognosis of patients with advanced heart failure (HF) remains grave. Renal dysfunction is a common comorbid condition in HF and is associated with adverse outcomes. Current evidence indicates that intrinsic renal disease and inflammation in HF makes the kidney susceptible to hemodynamic compromise and congestion and contributes to a great extent to the development of renal dysfunction. Relief of congestion requires combination treatment with diuretics, neurohormonal antagonists, and occasionally vasodilators as well as inotropes. However, high doses of diuretics may accelerate the development of renal dysfunction by increasing neurohumoral activity and inducing renal structural and functional changes. Ultrafiltration should be reserved for patients with true diuretic resistance. Finally, early identification of the "patient at risk" remains a challenging issue and is limited by the currently used conventional parameters of renal function. However, novel biomarkers of acute kidney ischemia and/or injury are emerging and promise to become a diagnostic option for this patient population., (© 2011 Wiley Periodicals, Inc.)

Aim: The aims of this study were to evaluate: i) the prevalence of impaired coronary flow reserve (CFR), ii) the association of impaired CFR with indices of left ventricular function, and iii) the independent predictors of impaired CFR in a cohort of high-risk asymptomatic individuals., Methods: Ninety-nine consecutive individuals (age, 52.5 ± 13.2 years; 68% male; left ventricular ejection fraction, 62 ± 6%) with at least one major cardiovascular risk factor (49% hypertension, 23% diabetes mellitus, 42% hypercholesterolemia, 32% smoking) were evaluated. Based on CFR values, patients were divided into normal (CFR ≥2.5), borderline (2.5>CFR ≥2.0), and abnormal (CFR < 2.0). Left ventricular function was assessed with comprehensive transthoracic echocardiography., Results: Impaired CFR was identified in 39 individuals (borderline, n = 25; abnormal, n = 14). Isovolumic relaxation time was significantly increased for abnormal compared with normal CFR (94 ± 12 vs. 85 ± 11 msec, p < 0.05), as was the left atrial volume index (LAVI) (24 ± 7 cm(3)/m(2) vs. 19.1 ± 5.2, p < 0.01). A stepwise linear regression analysis identified the LAVI and the deceleration time of E wave of transmitral flow as the only independent predictors of CFR value. An ordinal regression analysis model revealed two predictors of CFR categorization: diabetes mellitus (proportional odds ratio (POR) for CFR group deterioration, 4.55; 95% confidence interval (CI), 1.13-18.28; p = 0.033) and LAVI (POR, 1.11 per 1 cm(3)/m(2) increment; 95% CI, 1.01-1.23; p = 0.034)., Conclusions: CFR is often impaired among asymptomatic individuals with major cardiovascular risk factors and is associated with changes in left ventricular diastolic function and left atrial size. The prognostic importance of these early derangements should be assessed in prospective studies.

A shared understanding of medical conditions between patients and their health care providers may improve self-care and outcomes. In this study, the concordance between responses to a medical history self-report (MHSR) form and the corresponding provider documentation in electronic health records (EHRs) of 19 select co-morbidities and habits in 230 patients with heart failure were evaluated. Overall concordance was assessed using the κ statistic, and crude, positive, and negative agreement were determined for each condition. Concordance between MHSR and EHR varied widely for cardiovascular conditions (κ = 0.37 to 0.96), noncardiovascular conditions (κ = 0.06 to 1.00), and habits (κ = 0.26 to 0.69). Less than 80% crude agreement was seen for history of arrhythmias (72%), dyslipidemia (74%), and hypertension (79%) among cardiovascular conditions and lung disease (70%) and peripheral arterial disease (78%) for noncardiovascular conditions. Perfect agreement was observed for only 1 of the 19 conditions (human immunodeficiency virus status). Negative agreement >80% was more frequent than >80% positive agreement for a condition (15 of 19 [79%] vs 8 of 19 [42%], respectively, p = 0.02). Only 20% of patients had concordant MSHRs and EHRs for all 7 cardiovascular conditions; in 40% of patients, concordance was observed for ≤5 conditions. For noncardiovascular conditions, only 28% of MSHR-EHR pairs agreed for all 9 conditions; 37% agreed for ≤7 conditions. Cumulatively, 39% of the pairs matched for ≤15 of 19 conditions. In conclusion, there is significant variation in the perceptions of patients with heart failure compared to providers' records of co-morbidities and habits. The root causes of this variation and its impact on outcomes need further study., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Patients with heart failure (HF) are hospitalized over a million times annually in the United States. Hospitalization marks a fundamental change in the natural history of HF, leading to frequent subsequent rehospitalizations and a significantly higher mortality compared with nonhospitalized patients. Three-fourths of all HF hospitalizations are due to exacerbation of symptoms in patients with known HF. One-half of hospitalized HF patients experience readmission within 6 months. Preventing HF hospitalization and rehospitalization is important to improve patient outcomes and curb health care costs. To implement cost-effective strategies to contain the HF hospitalization epidemic, optimal schemes to identify high-risk individuals are needed. In this review, we describe the risk factors that have been associated with hospitalization risk in HF and the various multimarker risk prediction schemes developed to predict HF rehospitalization. We comment on areas that represent gaps in our knowledge or difficulties in interpretation of the current literature, representing opportunities for future research. We also discuss issues with using HF readmission rate as a quality indicator., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Worsening renal function (WRF) and hypokalemia related to diuretic use for acute decompensated heart failure (ADHF) are common and associated with poor prognosis. Low-dose dopamine infusion improves renal perfusion; its effect on diuresis or renal function specifically in ADHF is not known., Methods and Results: Sixty consecutive ADHF patients (age 75.7 ± 11.2 years; 51.7% female; left ventricular ejection fraction 35.3 ± 12.1%) were randomized, after receiving a 40 mg intravenous furosemide bolus, to either high-dose furosemide (HDF, 20 mg/h continuous infusion for 8 hours) or low-dose furosemide combined with low-dose dopamine (LDFD, furosemide 5 mg/h plus dopamine 5 μg kg(-1) min(-1) continuous infusion for 8 hours). Both strategies were compared for total diuresis, WRF (defined as a rise in serum creatinine of >0.3 mg/dL from baseline to 24 hours), electrolyte balance, and 60-day postdischarge outcomes. Mean hourly excreted urine volume (272 ± 149 mL in HDF vs 278 ± 186 mL in LDFD group; P = .965) and changes in dyspnea score (Borg index: -4.4 ± 2.1 in HDF group vs -4.7 ± 2.0 in LDFD group; P = .575) during the 8 hours of protocol treatment were similar in the two groups. WRF was more frequent in the HDF (n = 9; 30%) than in the LDFD group (n = 2; 6.7%; P = .042). Serum potassium changed from 4.3 ± 0.5 to 3.9 ± 0.4 mEq/L at 24 hours (P = .003) in the HDF group and from 4.4 ± 0.5 to 4.2 ± 0.5 mEq/L at 24 hours (P = .07) in the LDFD group. Length of stay and 60-day mortality or rehospitalization rates (all-cause, cardiovascular, and worsening HF) were similar in the two groups., Conclusions: In ADHF patients, the combination of low-dose furosemide and low-dose dopamine is equally effective as high-dose furosemide but associated with improved renal function profile and potassium homeostasis., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We assessed the association between (CA)n repeat polymorphism of angiotensinogen (AGT), 250 base pair (bp) insertion/deletion (I/D) of angiotensin-converting enzyme (ACE), tetranucleotide repeat polymorphism (TCTG)n of renin (REN), (CT)n repeat polymorphism of the natriuretic peptide receptor A (NPRA) genes, and the presence and extent of coronary artery disease (CAD) in Greek patients with a history of myocardial infarction (MI). A total of 158 post-MI patients referred for coronary angiography were compared with 144 controls. The SS genotype of the AGT gene was related with an increased risk for 3-vessel CAD (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.05-3.61; P = .041), whereas the SL genotype was related with a decreased risk (OR, 0.44; 95% CI, 0.22-0.87; P = .019). Moreover, there was a trend for the SL genotype of the REN gene toward increased risk for CAD. There was a significant association between (CA)n polymorphism of the AGT gene and the extent of CAD in Greek patients with a history of MI.

Background: Little is known about the epidemiology of stroke in chronic systolic and diastolic heart failure (HF) patients in normal sinus rhythm (NSR) receiving angiotensin-converting enzyme (ACE) inhibitors. Because all HF patients in the Digitalis Investigation Group (DIG) trial (N=7788) were in NSR and nearly all were receiving ACE inhibitors, a survey-based stroke-sub-study was conducted but its findings have never been published., Methods: DIG investigators confirmed a total 222 cases of stroke of which 144 had neurological deficit ≥24 h. We used logistic regression models to determine predictors of incident stroke among all 7788 patients and predictors of neurological deficit ≥24 h and all-cause mortality among 222 stroke patients., Results: Age ≥65 years (adjusted odds ratio {AOR}, 1.36; 95% confidence interval {CI}, 1.02-1.80; P=0.035), nonwhite race (AOR, 0.65; 95% CI, 0.42-0.99; P=0.047), hypertension (AOR, 1.46; 95% CI, 1.11-1.94; P=0.008), diabetes mellitus (AOR, 1.37; 95% CI, 1.03-1.82; P=0.030), and cardiomegaly (AOR, 1.39; 95% CI, 1.03-1.86; P=0.030) were independent predictors of stroke. However, among those with stroke, nonwhites had higher odds of neurological deficits ≥24 h (AOR, 2.86; 95% CI, 1.01-8.07; P=0.047) and death (AOR, 3.28; 95% CI, 1.30-8.30; P=0.012)., Conclusion: Older age, hypertension, diabetes and cardiomegaly were associated with increased incidence of stroke among HF patients with NSR receiving ACE inhibitors. The association of race and stroke, however, was complex. While nonwhite race was associated with decreased risk of stroke, among those with stroke, nonwhite race was associated with increased stroke severity and mortality., (Published by Elsevier Ireland Ltd.)

Introduction: Ischemic heart disease (IHD) is common in heart failure (HF), yet the association between incident coronary revascularization and mortality in these patients has not been examined in a propensity-matched study., Methods: In the Digitalis Investigation Group trial, 2853 patients without coronary revascularization and 120 patients with coronary revascularization during the first three years were alive at the end of three years. We used propensity scores to match 119 and 357 patients with and without coronary revascularization. Matched Cox regression models were used to estimate hazard ratio (HR) and 95% confidence interval (CI) for mortality during the fourth year of follow-up, for all patients and by the mean left ventricular ejection fraction (LVEF) of 35%., Results: Coronary revascularization was associated with higher mean LVEF (36% versus 32%; p<0.0001) and prevalence of angina pectoris (48% versus 32%; p<0.0001) but fewer prior myocardial infarction (80% versus 87%; p=0.023), all of which were balanced post-match. All-cause mortality occurred in 5.9% and 6.2% patients respectively with and without coronary revascularization (HR for coronary revascularization, 0.95; 95% CI, 0.39-2.32; p=0.910). HR for mortality associated with coronary revascularization for patients with LVEF < or = 35% and >35% were respectively 1.34 (95% CI, 0.48-3.71; p=0.578) and 0.61 (95% CI, 0.13-2.87; p=0.532)., Conclusion: Chronic HF patients with IHD receiving coronary revascularization were more likely to have angina and higher LVEF. However, in a balanced propensity-matched cohort, there was no association between coronary revascularization and mortality. The LVEF-associated variation in mortality needs to be prospectively studied., (Published by Elsevier Ireland Ltd.)

Background: Incremental value of echocardiography over clinical parameters for outcome prediction in advanced heart failure (HF) is not well established., Methods and Results: We evaluated 223 patients with advanced HF receiving optimal therapy (91.9% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, 92.8% beta-blockers, 71.8% biventricular pacemaker, and/or defibrillator use). The Seattle Heart Failure Model (SHFM) was used as the reference clinical risk prediction scheme. The incremental value of echocardiographic parameters for event prediction (death or urgent heart transplantation) was measured by the improvement in fit and discrimination achieved by addition of standard echocardiographic parameters to the SHFM. After a median follow-up of 2.4 years, there were 38 (17.0%) events (35 deaths; 3 urgent transplants). The SHFM had likelihood ratio (LR) chi(2) 32.0 and C statistic 0.756 for event prediction. Left ventricular end-systolic volume, stroke volume, and severe tricuspid regurgitation were independent echocardiographic predictors of events. The addition of these parameters to SHFM improved LR chi(2) to 72.0 and C statistic to 0.866 (P < .001 and P=.019, respectively). Reclassifying the SHFM-predicted risk with use of the echocardiography-added model resulted in improved prognostic separation., Conclusions: Addition of standard echocardiographic variables to the SHFM results in significant improvement in risk prediction for patients with advanced HF.