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Background: The HeartLogic algorithm (Boston Scientific, St Paul, MN) integrates data from implantable cardioverter-defibrillator (ICD) sensors to predict heart failure (HF) decompensation: first (S1) and third (S3) heart sounds, intrathoracic impedance, respiration rate, ratio of respiration rate to tidal volume (RSBI), and night heart rate., Objective: This study assessed the relative changes in ICD sensors at the onset of HeartLogic alerts, their association with patient characteristics, and outcomes., Methods: The study included 568 patients with HF carrying ICDs (CRT-D, n = 410) across 26 centers, with a median follow-up of 26 months. HeartLogic alerts triggered patient contact and potential treatment., Results: A total of 1200 HeartLogic alerts were recorded in 370 patients. The sensor with the highest change at the alert's onset was S3 in 27% of alerts, followed by S3/S1 (25%). Patients with atrial fibrillation (AF) and chronic kidney disease (CKD) at implantation had higher prevalence of alerts (AF, 84% vs no AF, 58%; CKD, 72% vs no CKD, 59%; P < .05) and rate (AF, 1.51 per patient-year vs no AF, 0.88 per patient-year; CKD, 1.30 per patient-year vs no CKD, 0.89 per patient-year; P < .05). During follow-up, 247 patients experienced more than 1 alert; in 85%, the sensor with the highest change varied between successive alerts. Of the 88 (7%) alerts associated with HF hospitalization or death, respiration rate or RSBI (11%, P = .007 vs S3/S1) and night heart rate (11%, P = .031 vs S3/S1) were more commonly the sensors showing the highest change. Clinical events were more common with the first alert (12.6%) than subsequent alerts (5.2%, P < .001)., Conclusion: HeartLogic alerts are mostly triggered by changes in heart sounds, but clinical events are more linked to respiration rate, RSBI, and night heart rate. Recurrent alerts often involve different sensors, indicating diverse mechanisms of HF progression., Competing Interests: Disclosures Dr Dello Russo is consultant for Abbott, Biosense Webster, and Boston Scientific. Dr Santini is consultant for Abbott, Boston Scientific, Medtronic, and Biotronik and is a speaker for Medtronic, Boston Scientific, Abbott, Microport, and Biotronik. Dr Bertini is a consultant for Boston Scientific and Microport; speaker and tutor in training courses for Boston Scientific, Microport, Medtronic, Abbott, Biotronik, Pfizer, Bayer, Daiichi-Sankyo, and Boehringer Ingelheim. Dr Casella has received speaker honoraria from Biosense Webster. Dr Averina, Dr Campari, and Dr Valsecchi are employees of Boston Scientific. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The cardiotoxic effects of anthracyclines therapy are well recognized, both in the short and long term. Echocardiography allows monitoring of cancer patients treated with this class of drugs by serial assessment of left ventricle ejection fraction (LVEF) as a surrogate of systolic function. However, changes in myocardial function may occur late in the process when cardiac damage is already established. Novel cardiac magnetic resonance (CMR) parametric techniques, like native T1 mapping and extra-cellular volume (ECV), may detect subclinical myocardial damage in these patients, recognizing early signs of cardiotoxicity before development of overt cancer therapy-related cardiac dysfunction (CTRCD) and prompting tailored therapeutic and follow-up strategies to improve outcome., Methods and Results: We conducted a systematic review and a meta-analysis to investigate the difference in CMR derived native T1 relaxation time and ECV values, respectively, in anthracyclines-treated cancer patients with preserved EF versus healthy controls. PubMed, Embase, Web of Science and Cochrane Central were searched for relevant studies. A total of 6 studies were retrieved from 1057 publications, of which, four studies with 547 patients were included in the systematic review on T1 mapping and five studies with 481 patients were included in the meta-analysis on ECV. Three out of the four included studies in the systematic review showed higher T1 mapping values in anthracyclines treated patients compared to healthy controls. The meta-analysis demonstrated no statistically significant difference in ECV values between the two groups in the main analysis (Hedges´s g =3.20, 95% CI -0.72-7.12, p =0.11, I 2 =99%), while ECV was significantly higher in the anthracyclines-treated group when sensitivity analysis was performed., Conclusions: Higher T1 mapping and ECV values in patients exposed to anthracyclines could represent early biomarkers of CTRCD, able to detect subclinical myocardial changes present before the development of overt myocardial dysfunction. Our results highlight the need for further studies to investigate the correlation between anthracyclines-based chemotherapy and changes in CMR mapping parameters that may guide future tailored follow-up strategies in this group of patients., Competing Interests: Declaration of competing interest CBD is the chief executive officer (part-time) for the Society for Cardiovascular Magnetic Resonance (SCMR), she has received speakers’ fees from Circle Cardiovascular Imaging, Siemens Healthineers, Bayer and GE HealthCare. The other Authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts., Objectives: This study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. The 1-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates., Results: Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold., Conclusions: Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Cleland was supported by a British Heart Foundation Centre of Research Excellence (grant number RE/18/6/34217). Dr Bozkurt has received consulting, advisory or research support from Abbott Vascular, Amgen, AstraZeneca, Baxter Healthcare Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Liva Nova, Relypsa, Renovacor, Roche, Sanofi, scPharmaceuticals, and Vifor. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Edwards Lifesciences, Medtronic, Novartis, Pharmacosmos, Roche, Laboratoires Servier, and Vifor. Drs Adamsson Eryd, Bodegård, Khordoc, and Zhang are employees of AstraZeneca. Dr Cleland has received grants and/or personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Bristol Myer Squibb, Idorsia, Johnson & Johnson, Medtronic, MyoKardia, NI Medical, Novartis, Pharmacosmos, Pharma Nord, Respicardia, Laboratoires Servier, Torrent Pharmaceuticals, Vifor, and VisCardia. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Vardeny has received personal or institutional research support from AstraZeneca. Dr Lund has received grant support, lecture fees, and/or consulting fees from Abbott Laboratories, Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Edwards Lifesciences, Lexicon Pharmaceuticals, Medscape, Merck Sharp & Dohme, MyoKardia, Novartis, OrionPharma, Pharmacosmos, Sanofi, and Vifor. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest L.C., M.I., Marika Casillo, N.P., R.S., R.R., and G.S. are stably employed by AMES, Centro Polidiagnostico Strumentale srl, Naples, Italy. O.G. is Staff Personnel (I3SNS Stable Researcher) of Xunta de Galicia (Servizo Galego de Saude -SERGAS-) through a research-staff contract (ISCIII)/SERGAS). O.G. also declares to be a member of RICORS Programme, RD21/0002/0025 via ISCIII and FEDER. O.G. receives grants for PI20/00902 funded by ISCIII and FEDER. O.G. is member of the COST Action CA21110 Building an open European network on osteoarthritis research (NetwOArk) funded by Eurpean Union under the European Cooperation in Science and technology Programme (COST). O.G. is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN) (GPC IN607B2022/03). A.O. declares travel, accommodations, expenses supported by Servier, and Astra Zeneca. A.O. declares expenses by Amgen and Servier. A.O. declares honoraria by Amgen, Bayer, Servier. A.O. received unconditional support for ESR-2121257 no-profit project by AstraZeneca. All these activities were unrelated and were performed outside of the submitted work. The other Authors do not have conflict of interests to declare related to the present work.

Background: Several implant-based remote monitoring strategies are currently tested to optimize heart failure (HF) management by anticipating clinical decompensation and preventing hospitalization. Among these solutions, the modern implantable cardioverter-defibrillator and cardiac resynchronization therapy devices have been equipped with sensors allowing continuous monitoring of multiple preclinical markers of worsening HF, including factors of autonomic adaptation, patient activity, and intrathoracic impedance., Objectives: We aimed to assess whether implant-based multiparameter remote monitoring strategy for guided HF management improves clinical outcomes when compared to standard clinical care., Methods: A systematic literature research for randomized controlled trials (RCTs) comparing multiparameter-guided HF management versus standard of care was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all-cause death and HF hospitalization events, whereas secondary endpoints included the individual components of the primary outcome., Results: Our meta-analysis included 6 RCTs, amounting to a total of 4869 patients with an average follow-up time of 18 months. Compared with standard clinical management, the multiparameter-guided strategy reduced the risk of the primary composite outcome (IRR 0.83, 95%CI 0.71-0.99), driven by statistically significant effect on both HF hospitalization events (IRR 0.75, 95%CI 0.61-0.93) and all-cause death (IRR 0.80, 95%CI 0.66-0.96)., Conclusion: Implant-based multiparameter remote monitoring strategy for guided HF management is associated with significant benefit on clinical outcomes compared to standard clinical care, providing a benefit on both hospitalization events and all-cause death., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Heart failure (HF) is a heterogeneous syndrome, and the specific sub-category HF with mildly reduced ejection fraction (EF) range (HFmrEF; 41-49% EF) is only recently recognised as a distinct entity. Cluster analysis can characterise heterogeneous patient populations and could serve as a stratification tool in clinical trials and for prognostication. The aim of this study was to identify clusters in HFmrEF and compare cluster prognosis., Methods and Results: Latent class analysis to cluster HFmrEF patients based on their characteristics was performed in the Swedish HF registry (n = 7316). Identified clusters were validated in a Dutch cross-sectional HF registry-based dataset CHECK-HF (n = 1536). In Sweden, mortality and hospitalisation across the clusters were compared using a Cox proportional hazard model, with a Fine-Gray sub-distribution for competing risks and adjustment for age and sex. Six clusters were discovered with the following prevalence and hazard ratio with 95% confidence intervals (HR [95%CI]) vs. cluster 1: 1) low-comorbidity (17%, reference), 2) ischaemic-male (13%, HR 0.9 [95% CI 0.7-1.1]), 3) atrial fibrillation (20%, HR 1.5 [95% CI 1.2-1.9]), 4) device/wide QRS (9%, HR 2.7 [95% CI 2.2-3.4]), 5) metabolic (19%, HR 3.1 [95% CI 2.5-3.7]) and 6) cardio-renal phenotype (22%, HR 2.8 [95% CI 2.2-3.6]). The cluster model was robust between both datasets., Conclusion: We found robust clusters with potential clinical meaning and differences in mortality and hospitalisation. Our clustering model could be valuable as a clinical differentiation support and prognostic tool in clinical trial design., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The HeartLogic algorithm (Boston Scientific) has proved to be a sensitive and timely predictor of impending heart failure (HF) decompensation., Objective: The purpose of this study was to determine whether remotely monitored data from this algorithm could be used to identify patients at high risk for mortality., Methods: The algorithm combines implantable cardioverter-defibrillator (ICD)-measured accelerometer-based heart sounds, intrathoracic impedance, respiration rate, ratio of respiration rate to tidal volume, night heart rate, and patient activity into a single index. An alert is issued when the index crosses a programmable threshold. The feature was activated in 568 ICD patients from 26 centers., Results: During median follow-up of 26 months [25th-75th percentile 16-37], 1200 alerts were recorded in 370 patients (65%). Overall, the time IN-alert state was 13% of the total observation period (151/1159 years) and 20% of the follow-up period of the 370 patients with alerts. During follow-up, 55 patients died (46 in the group with alerts). The rate of death was 0.25 per patient-year (95% confidence interval [CI] 0.17-0.34) IN-alert state and 0.02 per patient-year (95% CI 0.01-0.03) OUT of the alert state, with an incidence rate ratio of 13.72 (95% CI 7.62-25.60; P <.001). After multivariate correction for baseline confounders (age, ischemic cardiomyopathy, kidney disease, atrial fibrillation), the IN-alert state remained significantly associated with the occurrence of death (hazard ratio 9.18; 95% CI 5.27-15.99; P <.001)., Conclusion: The HeartLogic algorithm provides an index that can be used to identify patients at higher risk for all-cause mortality. The index state identifies periods of significantly increased risk of death., (Copyright © 2023. Published by Elsevier Inc.)

Background: In patients with established cardiovascular disease (CVD), the relation between metabolic syndrome (MetS) and incident heart failure (HF) in the absence of diabetes mellitus (DM) is largely unknown. This study assessed this relation in non-diabetic patients with established CVD., Methods: Patients from the prospective UCC-SMART cohort with established CVD, but without DM or HF at baseline were included (n = 4653). MetS was defined according to the Adult Treatment Panel III criteria. Insulin resistance was quantified using the homeostasis model of insulin resistance (HOMA-IR). The outcome was a first hospitalization for HF. Relations were assessed using Cox proportional hazards models adjusted for established risk factors: age, sex, prior myocardial infarction (MI), smoking, cholesterol, and kidney function., Results: During a median follow-up of 8.0 years, 290 cases of incident HF were observed (0.81/100 person years). MetS was significantly related to an increased risk of incident HF independent of established risk factors (hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.04-1.68, HR per criterion 1.17; 95% CI 1.06-1.29), as was HOMA-IR (HR per standard deviation [SD] 1.15; 95% CI 1.03-1.29). Of the individual MetS components, only higher waist circumference independently increased the risk of HF (HR per SD 1.34; 95% CI 1.17-1.53). Relations were independent of the occurrence of interim DM and MI, and were not significantly different for HF with reduced vs preserved ejection fraction., Conclusion: In CVD patients without a current diagnosis of DM, MetS and insulin resistance increase the risk of incident HF independent of established risk factors., Competing Interests: Conflict of interest Dr. Savarese reported grants and personal fees from Vifor, grants and non-financial support from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants and personal fees from Novartis, grants and personal fees from Cytokinetics, personal fees from Medtronic, grants from Boston Scientific, grants and personal fees from Pharmacosmos, grants from Merck, grants from Bayer, personal fees from Edwards, and funding through the Horizon 2022 program, outside the submitted work. Other authors declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We aimed to evaluate patient preferences towards three oral antihyperglycaemic therapies using conjoint analysis to determine which attributes may influence use., Methods: We used an online survey, completed by 553 US respondents with type 2 diabetes mellitus (T2DM; mean age 64 ± 9 years; 55% had cardiovascular [CV] risk; 27% had CV disease), to present hypothetical, blinded, pairwise, drug profile comparison choices, between different benefit/risk attributes and effect ranges. Attributes were derived from phase 3 trials for empagliflozin 25 mg (SGLT2 inhibitor), oral semaglutide 14 mg (GLP-1 receptor agonist) and sitagliptin 100 mg (DPP-4 inhibitor). Predicted therapy preference outcomes and relative importance of each attribute were calculated (presented as a percentage)., Results: Preference score was highest for the profile matching empagliflozin (56%), versus sitagliptin (38%; z-test, P < 0.001) and oral semaglutide (6%, z-test, P < 0.001). Results were overall consistent in subgroup analyses. Genital infection risk was the most important attribute (relative score: 19% [z-test, P = 0.077]). Other important attributes were fasting requirements (15%), weight reduction (15%), risk of vomiting (14%), CV benefit (12%), and risk of nausea (11%). HbA1c reduction (8%) and ability to take medication with other drugs (6%) were considered less important. While blinded to drug name/dose, respondents chose a drug profile similar to empagliflozin (41%) versus sitagliptin (31%), oral semaglutide (11%), or 'none of the options' (17%)., Conclusion: While the drug profile comparable to empagliflozin was preferred, CV benefit was not the top patient priority. A shared physician-patient decision model and increased patient education are needed to ensure optimal use of guideline-directed T2DM therapies., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice., Objectives: This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose., Results: Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively., Conclusions: Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Medtronic, Pharmacosmos, Roche, Servier, and Vifor. Dr Vardeny has received personal or institutional research support from AstraZeneca. Drs Adamsson Eryd and Bodegård are employees of AstraZeneca. Dr Lund has received grant support, lecture fees, and consulting fees from AstraZeneca. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Bozkurt has received consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, scPharmaceuticals, Baxter, Sanofi, Relypsa, Vifor, Roche, and Boehringer Ingelheim; has served on the steering committees of Relypsa and Renovacor; has served on a Clinical Event Committee for Abbott Pharmaceuticals; and has served on the Data Safety Monitoring Board for LivaNova Pharmaceuticals. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Differences in clinically important thresholds in patient-reported outcomes measures such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) remain less well-established in patients with heart failure with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF)., Objectives: The purpose of this study was to estimate meaningful thresholds for improvement or deterioration in the KCCQ-Total Symptom Score (TSS) in patients with HFrEF versus HFpEF., Methods: This secondary analysis of EMPERIAL program used anchor- and distribution-based approaches to estimate thresholds for improvement or deterioration in the KCCQ-TSS using Patient Global Impression of Severity (PGIS) as the primary anchor. Mean change in KCCQ-TSS from baseline to week 12 was calculated for each PGIS., Results: A total of 312 HFrEF and 315 HFpEF patients were enrolled. At week 12, mean changes in KCCQ-TSS corresponding to PGIS changes of "any improvement," "1-category improvement," and "1-category deterioration" were 13 ± 17, 12 ± 17, -3 ± 16 points in HFrEF, and 15 ± 18, 13 ± 17, -7 ± 18 points in HFpEF. Threshold for meaningful within-patient change in KCCQ-TSS was ≥9 points in HFrEF and ≥7 points in HFpEF patients. Sensitivity and specificity of ≥9 points/≥7 points change was 0.65 and 0.70 for HFrEF and 0.64 and 0.66 for HFpEF. Cumulative distribution function curves of KCCQ-TSS change from baseline to week 12 showed a shift to higher scores in both HFrEF and HFpEF patients., Conclusions: In the EMPERIAL program, a change in KCCQ-TSS of ≥9 points in HFrEF and ≥7 points in HFpEF represents the minimal clinically important difference for improvement, confirming the broad range of 5-10 points as meaningful thresholds., Competing Interests: Funding Support and Author Disclosures The EMPERIAL trials were sponsored by Boehringer Ingelheim. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Lindenfeld has received personal fees from Abbott, AstraZeneca, Boehringer Ingelheim, CVRx, Edwards Lifesciences, Impulse Dynamics, and V-Wave Ltd; and has received grants from AstraZeneca, Sensible Medical, and Volumetrix. Dr Abraham has received personal fees from Boehringer Ingelheim; has received consulting fees from Abbott, Respicardia, Sensible Medical, CVRx, and Impulse Dynamics; and has received salary support from V-Wave Ltd. Dr Savarese has received grants and personal fees from Vifor and AstraZeneca; has received grants and nonfinancial support from Boehringer Ingelheim; has received personal fees from Società Prodotti Antibiotici, Roche, Servier, GENESIS, Cytokinetics, and Medtronic; and has received grants from Merck Sharp & Dohme, and Novartis. Drs Salsali, Zeller, and Peil are employees of Boehringer Ingelheim. Dr Filippatos has received Committee Member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, and Boehringer Ingelheim. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squib, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; and has received personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, ID, and Cardiac Dimensions. Dr Khan has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension is common in patients with heart failure (HF), but less is known about resistant hypertension., Objectives: This study sought to investigate apparent treatment-resistant hypertension (aTRH) in patients with HF in the SwedeHF (Swedish Heart Failure Registry), across the spectrum of HF phenotypes (heart failure with reduced ejection fraction [HFrEF], heart failure with mildly reduced ejection fraction [HFmrEF], and heart failure with preserved ejection fraction [HFpEF])., Methods: aTRH was defined as systolic blood pressure ≥140 mm Hg (≥135 mm Hg in diabetes) despite treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or sacubitril-valsartan, as well as a calcium-channel blocker and a diuretic; non-treatment-resistant hypertension (TRH) was defined as systolic blood pressure above these thresholds but not on the 3-drug combination; and normal blood pressure was defined as under these thresholds. In each left ventricular ejection fraction (LVEF) category, patient factors associated with aTRH and non-TRH and outcomes (HF hospitalization and cardiovascular death composite, its components, and all-cause death) according to hypertension category were examined., Results: Among 46,597 patients, aTRH was present in 2,693 (10%), 1,514 (14%), and 1,450 (17%) patients with HFrEF, HFmrEF, and HFpEF, respectively. Older age, obesity, diabetes, and kidney disease were associated with a greater likelihood of aTRH and non-TRH (vs normal blood pressure). Associations were generally similar irrespective of LVEF category. Compared with normal blood pressure, aTRH was associated with a lower adjusted risk of the composite outcome in HFrEF and HFmrEF (HR: 0.79 [95% CI: 0.74-0.85] and HR: 0.86 [95% CI: 0.77-0.96]) but not in HFpEF (HR: 0.93 [95% CI: 0.84-1.04])., Conclusions: aTRH was most common in HFpEF and least common in HFrEF. Associated patient characteristics were similar irrespective of LVEF category. aTRH (vs normal blood pressure) was associated with a lower risk of first HF hospitalization or cardiovascular death in HFrEF and HFmrEF but not in HFpEF., Competing Interests: Funding Support and Author Disclosures SwedeHF is funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, and the Swedish Heart-Lung Foundation. No funding agency had any role in the design, conduct, or decision or approval to publish this study. Dr Lund is supported by Karolinska Institutet, the Swedish Research Council (grant 523-2014-2336), the Swedish Heart Lung Foundation (grants 20150557 and 20190310), and the Stockholm County Council (grants 20170112 and 20190525). Dr Jackson is supported by a British Heart Foundation Clinical Research Training Fellowship (FS/18/14/33330). Drs McMurray and Petrie are supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217). Dr Petrie has received lecture fees from AstraZeneca and Eli Lilly; personal fees from Novo Nordisk, AstraZeneca, NAPP Pharmaceuticals, Takeda Pharmaceutical, Alnylam, Bayer, Resverlogix, and Cardiorentis; and grants and personal fees from Boehringer Ingelheim and Novartis. Dr Jhund has received personal fees from Novartis and AstraZeneca; personal fees and grants from Boehringer Ingelheim; and his employer, the University of Glasgow, has received remuneration from AstraZeneca for work on the DAPA-HF and DELIVER trials. Mr Dahlström has received research grants from AstraZeneca, Pfizer, Boehringer Ingelheim, Boston Scientific, Vifor Pharma, and Roche Diagnostics; and consulting honoraria from Novartis, Amgen, AstraZeneca, and Pfizer all outside of the submitted work. Ms Hage has received consulting fees from Novartis and Roche Diagnostics; and speaker and honoraria from Merck Sharp & Dohme, and is supported by the Swedish Research Council (grant 20180899). Mr Savarese has received grants and personal fees from Vifor; grants and nonfinancial support from Boehringer Ingelheim; personal fees from Società Prodotti Antibiotici; grants and personal fees from AstraZeneca; personal fees from Roche, Servier, GENESIS, Cytokinetics, and Medtronic; and grants from Novartis, Boston Scientific, PHARMACOSMOS, and Merck, outside the submitted work. Dr McMurray reports that his employer, Glasgow University, has been paid by Novartis for his serving as an executive committee member and co–principal investigator of the ATMOSPHERE, PARADIGM-HF, and PARAGON-HF trials and as an executive/steering committee member of the PARADISE-MI and PERSPECTIVE trials (with sacubitril-valsartan) and for meetings/presentations related to these trials, aliskiren, and sacubitril-valsartan. Novartis has also paid for his travel and accommodation for some of these meetings. Glasgow University has also been paid by Novartis for Dr McMurray serving on an advisory board; by Bayer for serving as a steering committee member of the PANACHE trial using neladenoson bialanate (BAY 1067197); by Cardiorentis for serving as a steering committee member and endpoint committee chair for the TRUE-AHF trial and attending meetings related to this trial; by Cardiorentis for travel and accommodation to attend some of these meetings; by Amgen for serving as a steering committee member for the ATOMIC-HF and COSMIC-HF trials and attending meetings related to these trials; by Amgen for travel and accommodation for some of these meetings; by Oxford University (which received a grant from Bayer, which manufactures acarbose) for serving as a steering committee member for the ACE (Acarbose Cardiovascular Evaluation) trial (using acarbose) and attending meetings related to this trial; by Theracos for serving as principal investigator for the BEST trial and attending meetings related to this trial; by Theracos for travel and accommodation to attend some of these meetings; by AbbVie (which manufactures atrasentan) for serving as a steering committee member for the SONAR trial (using atrasentan) and to attend meetings related to this trial; by AbbVie for travel and accommodation to attend some of these meetings; by DalCor Pharmaceuticals for serving as a steering committee member for the Dal-GenE trial and to attend meetings related to this trial; by Pfizer for serving on the data safety monitoring committee for the SPIRE trial and to attend meetings related to this trial; by Merck for serving on the data safety monitoring committee for the MK-3102 program for the VICTORIA trial and for attending meetings related to this trial; by AstraZeneca (which markets dapagliflozin) for serving as principal investigator of DAPA-HF and co–principal investigator of DELIVER and to attend meetings related to these trials; by AstraZeneca for travel and accommodation to attend meetings; by GlaxoSmithKline for serving as co–principal investigator and steering committee member, respectively, for the Harmony-Outcomes trial (albiglutide) and 2 trials, ASCEND-D and ASCEND-ND, using daprodustat, and to attend meetings related to these trials; by GlaxoSmithKline for travel and accommodation to attend some of the meetings; by Bristol Myers Squibb for serving as a steering committee member for the STAND-UP clinical trial (using an HNO donor) on heart failure and to attend meetings related to this trial; by Kings College Hospital (which has received a grant from KRUK and Vifor-Fresenius, which manufacture intravenous iron) for serving as a steering committee member for the PIVOTAL trial (using intravenous iron) and for running the endpoint adjudication committee for this trial; and to attend meetings related to PIVOTAL and for travel and accommodation to attend some of the meetings. All payments were made through consultancies with Glasgow University, and Dr McMurray has not received any personal payments in relation to the trials or drugs. Dr Lund has received research grants from AstraZeneca, Novartis, Boehringer Ingelheim, Boston Scientific, Vifor Pharma, Relypsa, and Pharmacosmos; and consulting/speaker honoraria from AstraZeneca, Novartis, Bayer, Vifor Pharma, Sanofi, Lexicon, MyoKardia, Orion Pharma, Merck/Merck Sharp & Dohme, Respicardia, and Medscape. Ms Benson has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In heart failure (HF) patients, atrial fibrillation (AF) is associated with a worse prognosis. Implantable cardioverter-defibrillator (ICD) diagnostics allow continuous monitoring of AF and are equipped with algorithms for HF monitoring., Objective: We evaluated the association between the values of the multisensor HF HeartLogic index and the incidence of AF, and assessed the performance of the index in detecting follow-up periods of significantly increased AF risk., Methods: The HeartLogic feature was activated in 568 ICD patients. Median follow-up was 25 months [25th-75th percentile (15-35)]. The HeartLogic algorithm calculates a daily HF index and identifies periods of IN-alert state on the basis of a configurable threshold. The endpoints were daily AF burden ≥5 minutes, ≥6 hours, and ≥23 hours., Results: The HeartLogic index crossed the threshold value 1200 times. AF burden ≥5 minutes/day was documented in 183 patients (32%), ≥6 hours/day in 118 patients (21%), and ≥23 hours/day in 89 patients (16%). The weekly time of IN-alert state was independently associated with AF burden ≥5 minutes/day (hazard ratio [HR] 1.95; 95% confidence interval [CI] 1.22-3.13; P = .005), ≥6 hours/day (HR 2.66; 95% CI 1.60-4.44; P <.001), and ≥23 hours/day (HR 3.32; 95% CI 1.83-6.02; P <.001), after correction for baseline confounders. Comparison of the episode rates in the IN-alert state with those in the OUT-of-alert state yielded HR ranging from 1.57 to 3.11 for AF burden from ≥5 minutes to ≥23 hours., Conclusions: The HeartLogic alert state was independently associated with AF occurrence. The intervals of time defined by the algorithm as periods of increased risk of HF allow risk stratification of AF according to various thresholds of daily burden., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objective: Evidence suggests diabetes mellitus is an independent risk factor for adverse cardiovascular events in patients with heart failure. As a result, we sought to compare mortality in patients with heart failure with reduced ejection fraction (HFrEF) with and without diabetes., Research Design and Methods: The Veteran Affairs Hospitals' databases were queried to identify all veterans diagnosed with HFrEF from 2007 to 2015. From the overall sample of 165,159 veterans, 41,120 patients with diabetes were matched by their propensity scores (without replacement) 1:1 to non-diabetic patients. To estimate the association between diabetes (Type 1 and 2) and overall mortality of HFrEF patients, a Cox proportional hazard model was used on the matched sample and controlled for patient characteristics for a mean follow up of 3.6 years (standard deviation ±2.3)., Results: In a matched sample of 41,120 veterans with HFrEF with and without diabetes, those with diabetes and HFrEF were more often on guideline-directed medical therapy than those without diabetes. In the matched cohort, the mortality risk for patients with concurrent HFrEF and diabetes was 17.7% at 1 year and 74.3% at 5 years, whereas the mortality risk for those without diabetes was 15.3% at 1 year and 69.2% at 5 years. After controlling for patient characteristics such as age, sex, body mass index, heart rate, medical therapies, comorbidities, medications, low-density lipoproteins, high-density lipoproteins, we found that patients with diabetes compared to those without had a significantly increased risk of mortality (HR: 1.85, 95% CI: 1.77-1.92, p < 0.001)., Conclusions: Diabetic HFrEF patients have a higher risk of mortality than non-diabetic HFrEF patients despite controlling for medical therapies and comorbidities., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patients with heart failure (HF) are often cared for by non-cardiologists. The implications are unknown., Methods: In a nationwide HF cohort with reduced ejection fraction (HFrEF), we compared demographics, clinical characteristics, guideline-based therapy use and outcomes in non-cardiology vs. cardiology in-patient and out-patient care., Results: Between 2000 and 2016, 36,076 patients with HFrEF were enrolled in the Swedish HF registry (19,337 [54%] in-patients overall), with 44% of in-patients and 45% of out-patients managed in non-cardiology settings. Predictors of treatment in non-cardiology were age > 75 years (adjusted odds ratio for non-cardiology 1.20; 95% confidence interval 1.14-1.27), lower education level (0.71; 0.66-0.76 for university vs. compulsory), valve disease (1.24; 1.18-1.31) and systolic blood pressure (SBP) >120 mmHg (1.05; 1.00-1.10). Non-cardiology care was significantly associated with lower use of beta-blockers (0.80; 0.74-0.86) and devices (intracardiac defibrillator [ICD] and/or cardiac resynchronization therapy [CRT]: 0.63; 0.56-0.71), and less frequent specialist follow-up (0.61; 0.57-0.65). Over 1-year follow-up the risk of all-cause mortality (adjusted hazard ratio 1.09; 1.03-1.15) was higher but the risk of first HF (re-) hospitalization was lower (0.93; 0.89-0.97) in non-cardiology vs. cardiology care., Conclusions: In HFrEF, non-cardiology care was independently associated with older ageand lower education. After covariate adjustment, non-cardiology care was associated with lower use of beta-blockers and devices, higher mortality, and lower risk of HF hospitalization. Access to cardiology care may not be equitable and this may have implications for use of guideline-based care and outcomes., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Medications with proven benefit in patients with heart failure with reduced ejection fraction are recommended, according to prospective large clinical trials, in the stable patient after careful up-titration in a strict sequential order. Although the relevance of careful clinical up-titration is unproven, there is evidence that after recompensation and shortly after hospital discharge, the rate of cardiovascular death and hospitalization is high. Clinical studies provided evidence that the onset of treatment effects is rapid, occurring within 28 days with most of these drugs used, and in some trials, early treatment after discharge or already started in the hospital has provided benefits. Therefore, early treatment without deferring it to the stable outpatient may be useful to reduce cardiac-related events further. This expert opinion proposes treatment layering according to individual patient phenotypes involving heart rate, blood pressure, impaired renal function, and electrolyte disturbances, as well as dedicated subgroups of patients with specific requirements for treatment initiation. This complements other approaches that suggest starting sequential treatment according to the size of treatment effects of drugs, specific cardiac diseases, and patient wishes. Patient phenotyping may guide personalized drug layering in heart failure with reduced ejection fraction that provides the best outcomes, whereas pragmatic clinical trials are warranted to scrutinize the effectiveness of these approaches., Competing Interests: Funding Support and Author Disclosures Dr Allen has received grants from the American Heart Association, the National Institutes of Health, and the Patient-Centered Outcomes Research Institute; and consulting fees from Abbott, ACI Clinical, Amgen, Boston Scientific, Cytokinetics, and Novartis. Dr Abdin has received speaker honoraria from Novartis; and travel grants from Biotronik, Medtronic, and Novartis. Dr Lindenfeld has received grant funding from AstraZeneca, Sensible Medical, Volumetrix; and personal fees from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, and VWave. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; consultancy fees from service on the advisory board, steering committee, or executive committee of Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and holds a position as cofounder and nonexecutive director of Us2.ai. Dr Savarese has received grants from Boston Scientific (outside the submitted work), Vifor, Boehringer Ingelheim, AstraZeneca, and Novartis; nonfinancial support from Boehringer Ingelheim; and personal fees from Vifor and the Societá Prodotti Antibiotici, AstraZeneca, Roche, Servier, GENESIS, Cytokinetics, and Medtronic. Dr Gottlieb has received grants from Pfizer, Cytokinetics, and Amgen; and consulting for Cytokinetics. Dr Böhm has received support from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Servier, Medtronic, Vifor, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Comorbidities may differently affect treatment response and cause-specific outcomes in heart failure (HF) with preserved (HFpEF) vs. mid-range/mildly-reduced (HFmrEF) vs. reduced (HFrEF) ejection fraction (EF), complicating trial design. In patients with HF, we performed a comprehensive analysis of type 2 diabetes (T2DM), atrial fibrillation (AF) chronic kidney disease (CKD), and cause-specific outcomes., Methods and Results: Of 42,583 patients from the Swedish HF registry (23% HFpEF, 21% HFmrEF, 56% HFrEF), 24% had T2DM, 51% CKD, 56% AF, and 8% all three comorbidities. HFpEF had higher prevalence of CKD and AF, HFmrEF had intermediate prevalence of AF, and prevalence of T2DM was similar across the EF spectrum. Patients with T2DM, AF and/or CKD were more likely to have also other comorbidities and more severe HF. Risk of cardiovascular (CV) events was highest in HFrEF vs. HFpEF and HFmrEF; non-CV risk was highest in HFpEF vs. HFmrEF vs. HFrEF. T2DM increased CV and non-CV events similarly but less so in HFpEF. CKD increased CV events somewhat more than non-CV events and less so in HFpEF. AF increased CV events considerably more than non-CV events and more so in HFpEF and HFmrEF., Conclusion: HFpEF is distinguished from HFmrEF and HFrEF by more comorbidities, non-CV events, but lower effect of T2DM and CKD on events. CV events are most frequent in HFrEF. To enrich for CV vs. non-CV events, trialists should not exclude patients with lower EF, AF and/or CKD, who report higher CV risk., Competing Interests: Declaration of competing interest GS reports grants and personal fees from Vifor, non-financial support from Boehringer Ingelheim, personal fees from Societa´ Prodotti Antibiotici, grants from MSD, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants from Novartis, personal fees from GENESIS, personal fees from Medtronic, personal fees from Cytokinetics, outside the submitted work. LHL reports grants and personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Merck, personal fees from Sanofi, grants and personal fees from Vifor-Fresenius, grants and personal fees from AstraZeneca, grants and personal fees from Relypsa, personal fees from Bayer, grants from Boston Scientific, grants and personal fees from Novartis, personal fees from Pharmacosmos, personal fees from Abbott, grants and personal fees from Mundipharma, personal fees from Medscape, outside the submitted work. CS, BS, TT, IL, US, LB, FC, FA: None related with the current study. AM, SFF, MB, KGB and OV are employed by Boehringer Ingelheim., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Primary prevention implantable cardioverter defibrillator (ICD) is not generally recommended in New York Heart Association (NYHA) I class patients with dilated cardiomyopathy (DCM). This study sought to assess the competing risk of sudden cardiac death (SCD) in DCM patients with left ventricular ejection fraction (EF) ≤35% and NYHA I class., Methods: A total of 272 DCM patients with EF ≤35% and NYHA class I-III after ≥3 months of guideline-directed medical therapy were included. The risk of SCD and SCD/malignant ventricular arrhythmias (MVA) was assessed in NYHA I vs. NYHA II and NYHA III groups by competing risk analysis., Results: NYHA I patients were younger, had higher EF and smaller left atrium, were less likely receiving mineral corticoid receptor antagonists. The cumulative incidence of SCD (p = 0.92) and SCD/MVA (p = 0.42) did not differ between NYHA I vs NYHA II-III classes. NYHA class did not influence the association between ICD and SCD risk (p for interaction = 0.125)., Conclusions: In this cohort of DCMs, patients with EF ≤35% and NYHA I class were exposed to a risk of SCD and life-threatening arrhythmias not different from NYHA II-III. Therefore, inclusion of asymptomatic patients with DCM and systolic dysfunction should be strongly considered in future randomized studies on primary prevention ICD., Competing Interests: Declaration of competing interest None related to the current work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The role of anemia in heart failure with mid-range and preserved ejection fraction (HFmrEF, EF 40-49% and HFpEF, EF ≥50%) is unknown. We aimed to compare prevalence of, associations with, and prognostic role of anemia in HF across the EF spectrum., Methods: In patients from the Swedish HF Registry, we assessed the associations between clinical characteristics and anemia (hemoglobin <120 g/L in women and <130 g/L in men) by multivariable logistic regression, and between anemia, composite of all-cause death and HF hospitalization and all-cause death alone by multivariable Cox regression., Results: Of 49,985 patients with HF (anemia = 34%), 23% had HFpEF (anemia = 41%), 21% had HFmrEF (anemia = 35%) and 55% had HFpEF (anemia = 32%). Higher EF was independently associated with higher likelihood of concomitant anemia. Important predictors of anemia across the EF spectrum were male sex, older age, worse New York Heart Association class and renal function, lower systolic blood pressure, higher N-Terminal B-type natriuretic peptides levels, diabetes, valvular disease and in-patient status. Anemia had adjusted hazard ratios (95% CI) for mortality or HF hospitalization 1.24 (1.18-1.30) in HFpEF, 1.26 (1.19-1.34) in HFmrEF and 1.14 (1.10-1.19) in HFrEF; p interaction EF = 0.003; and for mortality 1.28 (1.20-1.36) in HFpEF, 1.21 (1.13-1.29) in HFmrEF, and 1.30 (1.24-1.35) in HFrEF; p interaction EF = 0.22., Conclusions: In this nation-wide registry, prevalence of anemia was higher in HFpEF vs. HFmrEF vs. HFrEF, but was associated with a similarly increased risk of death across the EF spectrum, with greater risk of death or HF hospitalization in HFpEF and HFmrEF vs. HFrEF., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The aim was to assess sex-specific differences in N-terminal B-type natriuretic peptide (NT-proBNP) regarding concentrations, predictors of high concentrations, and prognostic role, in a large and unselected population with chronic heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF)., Methods and Results: In 9847 outpatients with HFpEF, HFmrEF, and HFrEF (49 vs. 35 vs. 25% females, respectively) from the Swedish HF Registry, median NT-proBNP concentrations were 1598 ng/L in females vs. 1310 ng/L in males in HFpEF, 1764 vs. 1464 ng/L in HFmrEF, and 2543 vs. 2226 ng/L in HFrEF (p < 0.05 for all). The differences persisted after multiple adjustment. The largest sex-difference in NT-proBNP levels was observed in HFpEF with sinus rhythm, where median concentrations were 1.4 folds higher in females (923 vs. 647 ng/L). Independent predictors of NT-proBNP levels (defined as above the different medians according to sex and HF phenotype) were overall consistent across sexes and EF. NT-proBNP levels were similarly associated with risk of all-cause death/HF hospitalization in both sexes regardless of EF., Conclusion: Concentrations of NT-proBNP were higher in females across the EF spectrum, with larger relative differences in HFpEF with sinus rhythm. However, similar predictors of high levels were observed in both sexes. There were no sex-differences in the prognostic role of NT-proBNP. These findings support the use of NT-proBNP for prognostic purposes in chronic HF, regardless of sex., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: This study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum., Background: Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials., Methods: In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females., Results: Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF., Conclusions: Males and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the incidence, the predictors, and the associations with outcomes of changes in ejection fraction (EF) in heart failure (HF) patients., Background: EF determines therapy in HF, but information is scarce about incidence, determinants, and prognostic implications of EF change over time., Methods: Patients with ≥2 EF measurements were made in the Swedish Heart Failure Registry were categorized as heart failure with preserved ejection fraction (HFpEF) (EF ≥50%), heart failure with midrange ejection fraction (HFmrEF) (EF 40% to 49%), or heart failure with reduced ejection fraction (HFrEF) (EF <40%). Changes among categories were recorded, and associations among EF changes, predictors, and all-cause mortality and/or HF hospitalizations were analyzed using logistic and Cox regressions., Results: Of 4,942 patients at baseline, 18% had HFpEF, 19% had HFmrEF, and 63% had HFrEF. During follow-up, 21% and 18% of HFpEF patients transitioned to HFmrEF and HFrEF, respectively; 37% and 25% of HFmrEF patients transitioned to HFrEF and HFpEF, respectively; and 16% and 10% of HFrEF patients transitioned to HFmrEF and HFpEF, respectively. Predictors of increased EF included female sex, cases of less severe HF, and comorbidities. Predictors of decreased EF included diabetes, ischemic heart disease, and cases of more severe HF. Use of renin-angiotensin-system inhibitors was associated with lower likelihood of EF increase, but not with EF decrease, i.e., stable EF. Increased EF was associated with a lower risk (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.55 to 0.69) and decreased EF with a higher risk (HR: 1.15; 95% CI: 1.01 to 1.30) of mortality and/or HF hospitalizations. Prognostic implications were most evident for transitions to and from HFrEF., Conclusions: Increases in EF occurred in one-fourth of HFrEF and HFmrEF patients, and decreases occurred in more than one-third of patients with HFpEF and HFmrEF. EF change was associated with a wide range of important clinical and organizational factors as well as with outcomes, particularly transitions to and from HFrEF., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: This study investigated 1-year incidence and predictors of dyskalemia (dysK) and its outcome associations in heart failure with preserved ejection fraction (HFpEF), HF with mid-range EF (HFmrEF), and HF with reduced EF (HFrEF)., Background: DysK in real-world HF is insufficiently characterized. Fear of dyskalemia may lead to underuse or underdosing of renin-angiotensin-aldosterone system inhibitors., Methods: Patients enrolled in the SwedeHF (Swedish Heart Failure) Registry from 2006 to 2011 in Stockholm, Sweden were included in the analyses. Multivariate Cox regression analysis identified independent predictors of dysK within 1 year. Time-dependent Cox models assessed outcomes associated with incident dysK (all-cause death, HF, and other cardiovascular disease [CVD] hospitalizations) within 1 year from baseline., Results: Of 5,848 patients, 24.4% experienced hyperkalemia (hyperK [K >5.0 mmol/l]) at least once, and 10.2% had moderate or severe hyperK (K >5.5 mmol/l). Adjusted risk of moderate or severe hyperK was highest in HFpEF and HFmrEF. Similarly, 20.3% of patients had at least one episode of hypokalemia (hypoK [<3.5 mmol/l]), and 3.7% had severe hypoK (<3.0 mmol/l). Adjusted risk of any hypoK was highest in HFpEF. Independent predictors of both hyperK and hypoK were sex, baseline potassium and estimated glomerular filtration rate, low hemoglobin, chronic obstructive pulmonary disease (COPD), inpatient status, and higher New York Heart Association functional class. Incident dysK was associated with increased risk of mortality. Furthermore, hypoK was associated with increased CVD hospitalizations (HF-related excluded). There was no association between dysK and HF hospitalization risk, regardless of EF., Conclusions: DysK is common in HF and is associated with increased mortality. Risk of moderate or severe hyperK was highest in HFpEF and HFmrEF, whereas risk of hypoK was highest in HFpEF. HF severity, low hemoglobin, COPD, baseline high and low potassium, and low eGFR were relevant predictors of dysK occurrence., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Professional guidelines are based on the best available evidence. However, patients treated in clinical practice may differ from those included in reference trials., Objective: The aim of this study was to evaluate the effects of cardiac resynchronization therapy (CRT) in a large population of patients implanted with a CRT device stratified in accordance with the 2016 European heart failure (HF) guidelines., Methods: We collected data on 930 consecutive patients from the Cardiac Resynchronization Therapy MOdular REgistry. The primary end point was a composite of death and HF hospitalization., Results: Five hundred sixty-three (60.5%) patients met class I indications, 145 (15.6%) class IIa, 108 (11.6%) class IIb, and 114 (12.3%) class III. After a median follow-up of 1001 days, 120 (14.7%) patients who had an indication to CRT had died and 71 (8.7%) had been hospitalized for HF. The time to the end point was longer in patients with a class I indication (hazard ratio 0.55; 95% confidence interval 0.39-0.76; P = .0001). After 12 months, left ventricular (LV) end-systolic volume had decreased by ≥15% in 61.5% (320/520) of patients whereas in 57.5% (389/676) of patients the absolute LV ejection fraction improvement was ≥5%. Adherence to class I was also associated with an absolute LV ejection fraction increase of >5% (P = .0142) and an LV end-systolic volume decrease of ≥15% (P = .0055)., Conclusion: In our population, ∼60% of patients underwent implantation according to the 2016 European HF guidelines class I indication. Adherence to class I was associated with a lower death and HF hospitalization rates and better LV reverse remodeling., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to assess the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiovascular (CV) versus non-CV events and between NT-proBNP and potential treatment effects in heart failure (HF) with preserved, mid-range, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF, respectively) and clinically relevant subgroups., Background: Optimizing patient eligibility criteria in HF trials requires biomarkers that enrich for CV but not for non-CV events and select patients most likely to respond to the tested intervention., Methods: In the Swedish HF registry population stratified by EF category, we used Kaplan-Meier curves to estimate unadjusted CV and non-CV risks (mortality or hospitalization); Poisson regressions to calculate crude event rates of CV and non-CV events according to NT-proBNP levels; and Cox regressions to calculate the adjusted hazard ratios for HF therapies according to NT-proBNP ≤ or > median., Results: In a cohort of 15,849 patients (23% HFpEF, 21% HFmrEF, 56% HFrEF), median NT-proBNP was 2,037, 2,192, and 3,141 pg/ml, respectively. With increasing NT-proBNP, CV event rates increased more steeply than non-CV rates (range 20 to 160 and 30 to 100 per 100 patient-years in HFpEF; 20 to 130 and 20 to 100 in HFmrEF; and 20 to 110 and 20 to 50 in HFrEF, respectively). The CV-to-non-CV ratio increased with increasing NT-proBNP in HFpEF and HFrEF, but only in the lower range in HFmrEF. The association between treatments (e.g., angiotensin-converting enzyme-inhibitor, angiotensin II receptor blockers, and beta-blockers) and outcomes was consistent in NT-proBNP ≤ and > median., Conclusions: In HF trial design in different EF categories, NT-proBNP may be a useful tool for eligibility and enrichment for CV events, but its role in predicting a potential treatment response remains unclear., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events., Data Synthesis: MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807-1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385)., Conclusions: Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: In acute decompensated heart failure (ADHF) with preserved ejection fraction (HFpEF) there are no surrogate endpoints for early phase trials. The aim of the current study was to evaluate whether a reduction in natriuretic peptides (NP) between acute hospital presentation to stable follow-up is associated with improved mortality and morbidity., Methods: Patients presenting acutely to the hospital for ADHF with HFpEF enrolled in the Karolinska Rennes (KaRen) study and reporting N-terminal pro-B-type NP or B-type NP assessment at baseline hospital presentation and at 4-8weeks follow-up were prospectively studied. Logistic regression analyses were performed to detect the predictors of baseline and changes in NPs. Cox regression models were performed to assess the impact of NP reductions on mortality and the composite of mortality and HF hospitalization., Results: Of 361 patients (median follow-up 585days), 267 (74%) reported an improvement in NPs, while 94 (26%) reported worsening. At baseline, the independent predictors of lower NPs were higher glomerular filtration rate (Odds Ratio [OR] per unit: 1.013; 95% Confidence Interval [CI]: 1.005-1.021) and younger age (OR per year: 0.972; CI: 0.947-0.998). Improvement in NPs at follow-up was predicted by higher heart rate at baseline (OR per bpm: 1.014; CI: 1.003-1.025). After adjustments, the hazard ratio for all-cause death was 0.730 (CI: 0.456-1.169) and for the composite outcome 0.814 (CI: 0.582-1.139) for patients who improved vs. worsened in NP levels., Conclusions: In patients presenting acutely to the hospital with HFPEF, an improvement in NP levels did not independently and significantly predict improved mortality and/or morbidity. NPs as surrogate endpoints in acute HFpEF require further study., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study investigated the efficacy and safety of novel oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and heart failure (HF) by a meta-analysis., Background: AF is quite prevalent in patients with HF., Methods: Four phase III clinical trials comparing NOACs to warfarin in patients with AF were included. Each patient was defined as affected by HF according to the criteria of the trial in which the patient was enrolled. Pre-specified outcomes were the composite of stroke/systemic embolism (SSE); major, intracranial, and any bleeding; and cardiovascular (CV) and all-cause death., Results: A total of 55,011 patients were enrolled, 26,384 (48%) with HF, and 28,627 (52%) without HF; 27,518 receiving NOACs and 27,493 receiving warfarin (median, 70 years of age; 36% females; follow-up: 1.5 to 2.8 years). Rates of SSE (relative risk [RR]: 0.98; 95% confidence interval [CI]: 0.90 to 1.07]; p = 0.68) and major bleeding (RR: 0.95; 95% CI: 0.88 to 1.03; p = 0.21) were comparable in patients with and without HF. HF patients had reduced rates of any (RR: 0.86; 95% CI: 0.81 to 0.91; p < 0.01) and intracranial (RR: 0.74 95% CI: 0.63 to 0.88; p < 0.01) bleeding but increased rates of all-cause (RR: 1.70 95% CI: 1.31 to 2.19; p < 0.01) and CV death (RR: 2.05 95% CI: 1.66 to 2.55; p < 0.01). NOACs, compared with warfarin significantly reduced SSE and major, intracranial, and any bleeding, regardless of the presence or absence of HF (p interaction > 0.05 for each)., Conclusions: Patients with AF and HF had increased mortality but reduced rates of intracranial and any bleeding compared with the no-HF patients, with no differences in rates of SSE and major bleeding. NOACs significantly reduced SSE, major bleeding, and intracranial hemorrhage in HF patients. No interactions in efficacy and safety of NOACs were observed between AF patients with and without HF., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have investigated the association between native QRS duration (QRSd) or QRS narrowing and response to biventricular pacing. However, their results have been conflicting. The aim of our study was to determine the association between the relative change in QRS narrowing index (QI) and clinical outcome and prognosis in patients who undergo cardiac resynchronization therapy (CRT) implantation., Methods and Results: We included 311 patients in whom a CRT device was implanted in accordance with current guidelines for CRT. On implantation, the native QRS, the QRSd and the QI during CRT were measured. After 6months, 220 (71%) patients showed a 10% reduction in LVESV. The median [25th-75th] QI was 14.3% [7.2-21.4] and was significantly related to reverse remodeling (r=+0.22; 95%CI: 0.11-0.32, p=0.0001). The cut-off value of QI that best predicted LV reverse remodeling after 6months of CRT was 12.5% (sensitivity=63.6%, specificity=57.1%, area under the curve=0.633, p=0.0002). The time to the event death or cardiovascular hospitalization was significantly longer among patients with QI>12.5% (log-rank test, p=0.0155), with a hazard ratio (HR) of 0.3 [95%CI: 0.11-0.78]. In the multivariate regression model adjusted for baseline parameters, a 10% increment in QI (HR=0.61[0.44-0.83], p=0.002) remained significantly associated with CRT response., Conclusions: Patients with a larger decrease in QRSd after CRT initiation showed greater echocardiographic reverse remodeling and better outcome from death or cardiovascular hospitalization. QI is an easy-to-measure variable that could be used to predict CRT response at the time of pacing site selection or pacing configuration programming., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Dipeptidyl Peptidase 4 Inhibitors (DPP4-I) and Sodium-Glucose Linked coTransporter-2 Inhibitors (SGLT2-I) improve glycemic control in patients with type 2 diabetes mellitus (DM). However, only few studies were designed to assess the efficacy and safety of these drugs on cardiovascular (CV) events and mortality. The purpose of the current study was to evaluate the effects of DPP4-Is and SGLT2-Is on CV events and mortality by meta-analysis., Methods: Randomized trials enrolling more than 200 patients, comparing DPP-4-Is or SGLT2-Is versus placebo or active treatments in patients with DM, and reporting at least one event among all-cause and CV mortality, stroke, myocardial infarction (MI) and new onset of heart failure (HF), were included., Results: 157 randomized trials (114 on DPP4-Is and 43 on SGLT2-Is) enrolling 140,470 patients (107,100 in DPP4-I and 33,370 in SGLT2-I studies) were included in the analysis. Compared to control, treatment with DPP4-Is did not affect all-cause (RR: 1.010; 95% CI: 0.935-1.091) and CV (RR: 0.975; CI: 0.887-1.073) mortality as well as risk of MI (RR: 0.915; CI: 0.835-1.002), stroke (RR: 0.933; CI: 0.820-1.062) and HF (RR: 1.083; CI: 0.973-1.205). Treatment with SGLT2-Is significantly reduced the risk of all-cause death by 28% (RR: 0.718; CI: 0.613-0.840), CV death by 33% (RR: 0.668; CI: 0.544-0.821), MI by 20% (RR: 0.803; CI: 0.668-0.965) and HF by 35% (RR: 0.652; CI: 0.517-0.823) without effect on stroke (RR: 1.158; CI: 0.912-1.469)., Conclusions: DPP4-Is show a safe CV profile as they do not affect mortality and CV events, including HF, in patients with type 2 DM. SGLT2-Is are associated with improved CV outcome and survival in DM patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Angiotensin receptor blockers (ARBs) are a valuable option to reduce cardiovascular (CV) mortality and morbidity in cardiac patients in whom ACE-inhibitors (ACE-Is) cannot be used. However, clinical outcome data from direct comparisons between ACE-Is and ARBs are scarce, and some data have recently suggested superiority of ACE-Is over ARBs., Methods: We performed a Bayesian network-meta-analysis, with data from both direct and indirect comparisons, from 27 randomized controlled trials (RCTs), including a total population of 125,330 patients, to assess the effects of ACE-Is and ARBs on the composite endpoint of CV death, myocardial infarction (MI) and stroke, and on all-cause death, new-onset heart failure (HF) and new-onset diabetes mellitus (DM) in high CV risk patients without HF., Results: Using placebo as a common comparator, we found no significant differences between ACE-Is and ARBs in preventing the composite endpoint of CV death, MI and stroke (RR: 0.92; 95% CI 0.78-1.08). When components of the composite outcome were analysed separately, ACEi and ARBs were associated with a similar risk of CV death (RR: 0.92; 95% CI 0.73-1.10), MI (RR: 0.91; 95% CI 0.78-1.07) and stroke (RR: 0.97; 95% CI 0.79-1.19), as well as a similar incident risk of all-cause death (RR: 0.94; 95% CI 0.85-1.05), new-onset HF (RR: 0.92; 95% CI 0.77-1.15) and new-onset DM (RR: 99; 95% CI 0.81-1.21)., Conclusions: With the limitations of indirect comparisons, we found that in patients at high CV risk without HF, ARBs were similar to ACE-Is in preventing the composite endpoint of CV death, MI and stroke. Compared with ARBs, we found no evidence of statistical superiority for ACE-Is, as a class, in preventing incident risk of all-cause death, CV death, MI, stroke, new-onset DM and new-onset HF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The addition of ezetimibe to statin therapy has been widely demonstrated to significantly reduce low-density lipoprotein cholesterol levels. However, the efficacy of ezetimibe in reducing CV events and its safety has been less investigated. The aim of the current meta-analysis was to report efficacy and safety of ezetimibe from randomized clinical trials., Methods: Randomized clinical trials with a follow-up of at least 24 weeks, enrolling more than 200 patients, comparing ezetimibe versus placebo or ezetimibe plus another hypolipidemic agent versus the same hypolipidemic drug alone and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of cancer were included in the analysis., Results: 7 trials enrolling 31,048 patients (median follow-up 34.1 ± 26.3 months; 70% women; mean age 61 ± 8 years) were included in the analysis. Compared to control therapy, ezetimibe significantly reduced the risk of MI by 13.5% (RR: 0.865, 95% CI: 0.801 to 0.934, p<0.001) and the risk of any stroke by 16.0% (RR: 0.840, 95% CI: 0.744 to 0.949, p=0.005), without any effect on all-cause and CV mortality (RR: 1.003, 95% CI: 0.954 to 1.055, p=0.908; RR: 0.958, 95% CI: 0.879 to 1.044, p=0.330; respectively) and risk of new cancer (RR: 1.040, 95% CI: 0.965 to 1.120, p=0.303)., Conclusions: Ezetimibe significantly reduces the risk of MI and stroke without any effect on all-cause and CV mortality and risk of cancer., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are recommended in heart failure with reduced ejection fraction (HFREF), but there is limited data on ARB vs. ACE-I and their combination in unselected populations. The purpose of this study was to compare the associations between the use of ACE-I, ARB and their combination, and outcomes in HFREF., Methods and Results: We prospectively studied 22,947 patients with HFREF (ejection fraction<40%) enrolled in the Swedish Heart Failure Registry who received ACE-I but not ARB (n=15,801, 69%), ARB but not ACE-I (n=4335, 19%), their combination (n=571, 2%) or neither (n=2240, 10%). As compared with ACE-I alone, the hazard ratios (HRs) for ARB alone for all-cause mortality was 0.97 (95% CI=0.91-1.03; p=0.27), for HF hospitalization 1.08 (CI=1.02-1.15; p<0.01) and for the composite outcome 1.03 (CI=0.99-1.08; p=0.15). ACE-I and ARB combination had for death HR=0.98 (95% CI=0.84-1.14; p=0.76), for HF hospitalization HR=1.49 (CI=1.33-1.68; p<0.01) and for the composite outcome HR=1.35 (CI=1.21-1.50; p<0.01). Use of neither ACE-I nor ARB was associated with HR for death 1.41 (CI=1.33-1.50; p<0.01), for HF hospitalization 1.16 (CI=1.08-1.25; p<0.01) and for the composite outcome 1.28 (CI=1.21-1.35; p<0.01)., Conclusion: This large generalizable analysis confirms the current recommendation of using ACE-I as first choice in HFREF. ARB can be considered an alternative in patients who cannot use ACE-I but should not routinely replace ACE-I. The combination of ACE-I and ARB was not associated with additional benefit over either one alone, and may potentially be harmful., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4is) improve glucose control in patients with type 2 diabetes mellitus (DM); however, only few studies were properly designed to evaluate their cardiovascular (CV) effects. The purpose of this study was to assess the impact of DPP-4i treatment on CV morbidity and mortality., Methods: Randomized clinical trials enrolling more than 200 patients, comparing DPP-4 versus placebo or active treatments in patients with DM and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of heart failure (HF) were included in the analysis., Results: Ninety-four trials enrolling 85,224 patients (median follow-up=29weeks) were included in the analysis. Compared to control, treatment with DPP-4i did not affect all-cause and CV mortality, as well as stroke, in the short and long terms (< and >=29weeks, respectively). DPP-4i reduced the risk of MI in the short (RR: 0.584 [95% CI: 0.361 to 0.943]; p=0.028), but not in the long term. Additionally, long-term treatment with DPP-4 was associated with a 15.8% increased risk of HF (RR: 1.158 [CI: 1.011 to 1.326]; p=0.034). No heterogeneity among studies or publication bias was detected., Conclusions: DPP4is do not affect all cause- and CV-mortality and stroke in diabetic patients; the reduction in MI observed with short-term treatment does not persist in the long term. Long-term use of DPP-4i in diabetic patients is associated with increased risk of HF., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The adverse prognostic impact of metabolic syndrome (METS) in unselected populations and in patients with coronary heart disease has been previously shown. The aim of the current analysis was to evaluate the impact of METS on prognosis in chronic heart failure (HF)., Methods: International Diabetes Federation criteria were used for the diagnosis of METS. Adjusted Cox regression models with all-cause and HF death as outcomes were fitted in 6648 patients enrolled in GISSI-HF trial with no missing values for the variables of interest., Results: Risk of all-cause and HF death was significantly reduced in patients with METS compared to patients without METS (HR: 0.83, 95% CI: 0.72 to 0.95, p=0.005; HR: 0.76, 95% CI: 0.59 to 0.98, p=0.031; respectively). As compared with patients with no METS and no type 2 diabetes mellitus (DM), the risk of all-cause and HF death was significantly lower in patients with METS and no DM (HR: 0.76, 95% CI: 0.62 to 0.95, p=0.015; HR: 0.65, 95% CI: 0.42 to 0.99, p=0.046; respectively), whereas it was significantly increased in patients with DM and no METS (HR: 1.34, 95% CI: 1.21 to 1.48, p<0.001; HR: 1.44, 95% CI: 1.21 to 1.72, p<0.001; respectively). Patients with METS and DM showed no difference for risk of total and HF death compared with patients with no METS and no DM (HR: 1.03, 95% CI: 0.87 to 1.21, p=0.762; HR: 0.99; 95% CI: 0.73 to 1.35; p=0.963; respectively)., Conclusions: METS is associated with reduced all-cause and HF mortality in patients with HF. HF patients with DM without METS are at the highest risk of mortality, whereas METS attenuates mortality risk in HF patients with DM., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The association between C-reactive protein (CRP) levels and risk of cardiovascular (CV) events has been reported in several studies. However, it is unclear whether a reduction in CRP is associated with a reduction in risk of clinical events. Therefore we sought to investigate, in a meta-regression analysis of randomized studies enrolling patients treated by statins, whether changes in CRP are associated with changes in risk of CV events or overall survival., Methods: Randomized trials enrolling patients treated by statins, reporting CRP at baseline and at end of follow-up, CV events [myocardial infarction (MI) and stroke], CV and all-cause mortality were selected., Results: Twenty-two trials enrolling 54,213 participants were included in the analysis. Meta-analysis showed that active treatment significantly reduced risk of all-cause death by 8%, myocardial infarction by 11%, stroke by 10.3% and the composite outcome (including CV death, MI and stroke) by 8%, whereas risks of CV mortality was not significantly reduced. Meta-regression analysis revealed that reduction in CRP levels was significantly associated only with the reduction of MI, whereas no relationship was identified between changes in CRP and risk of stroke, CV and all-cause mortality, and the composite outcome., Conclusions: These findings demonstrate that statin-induced changes in CRP do not correlate with major CV events apart from the risk of MI nor with overall survival in high-risk patients. These data suggest that although CRP may be a surrogate marker for coronary risk, it should not be used for predicting the effectiveness of statin therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Aging is an independent risk factor for cardiovascular and cerebrovascular disease. To date, little is known about the mechanisms of aging of cerebral arteries and whether the aging gene p66(Shc) is implicated in it. The present study was designed to assess age-induced vascular dysfunction in cerebral and systemic arteries of wild type (wt) and p66(Shc-/-) mice., Methods: Basilar arteries and size matched second order femoral arteries of 3-month (3M), 6-month (6M) and 2-year old (2Y) mice were studied in wt and p66(Shc-/-) mice. To assess vascular function, arterial rings mounted in a myograph for isometric tension recordings were exposed to increasing concentrations of acetylcholine and sodium nitroprusside. Reactive oxygen species (ROS) generation was assessed in femoral and basilar arteries using the spin trap 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine., Results: In wt mice, endothelial function of the femoral artery was not affected by age unlike in the basilar artery where an age-dependent dysfunction was observed. In p66(Shc-/-) a similar response was observed in the femoral artery; however, age-dependent endothelial dysfunction of the basilar artery was blunted as compared to wt. Levels of ROS were comparable in the femoral arteries of 3M and 2Y of wt and p66(Shc-/-) mice. Differently, ROS levels in the basilar artery of wt mice were strongly increased by age unlike in p66(Shc-/-) mice where they remained comparable irrespective of age., Conclusions: Endothelial function in cerebral arteries, but not in size-matched systemic ones, is heavily impaired by aging. This process is paralleled by an increased ROS production and is mediated by the p66(Shc) gene., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)