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Background: Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF)., Methods: Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO 2 ]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers., Results: The ARISE-HF Trial is fully enrolled., Conclusions: This report describes the rationale and study design of ARISE-HF., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), although initially developed as glucose-lowering drugs, provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status. Integration of SGLT-2is into clinical practice requires practical guidance for physicians about their use. To overcome physicians' clinical inertia for SGLT-2i use, including addressing safety, potentially a barrier to their use, a roundtable discussion with physicians from three specialties (cardiology, endocrinology, and nephrology) was conducted. This review summarizes the physicians' clinical experience and recommendations about SGLT-2i use across different patient populations, taking into consideration the beneficial effects of SGLT-2is and their safety. The key aspects discussed regarding SGLT-2i safety include acute effects on kidney function (estimated glomerular filtration rate acute dip upon SGLT-2i initiation and acute kidney injury), volume depletion, diabetic ketoacidosis, genitourinary infections, hyperkalemia, and hypoglycemia. To mitigate any potential risks related to SGLT-2i safety, physicians can make minor adjustments to an individual patient's treatment plan, while retaining the SGLT-2i cardiorenal benefits for effective disease management. Recognition by physicians that the benefits of SGLT-2i use on clinical outcomes outweigh the risks will result in the integration of SGLT-2is into clinical practice and lead to improved patient care and outcomes.

Background: The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood., Objectives: The authors compared the management and outcomes of CS patients initially presenting to hub versus spoke hospitals within a regional care network., Methods: The authors stratified consecutive patients enrolled in their CS registry (January 2017 to December 2019) by presentation to a spoke versus the hub hospital. The primary endpoint was 30-day mortality. Secondary endpoints included bleeding, stroke, or major adverse cardiovascular and cerebrovascular events., Results: Of 520 CS patients, 286 (55%) initially presented to 34 spoke hospitals. No difference in mean age (62 years vs 61 years; P = 0.38), sex (25% vs 32% women; P = 0.10), and race (54% vs 52% white; P = 0.82) between spoke and hub patients was noted. Spoke patients more often presented with acute myocardial infarction (50% vs 32%; P < 0.01), received vasopressors (74% vs 66%; P = 0.04), and intra-aortic balloon pumps (88% vs 37%; P < 0.01). Hub patients were more often supported with percutaneous ventricular assist devices (44% vs 11%; P < 0.01) and veno-arterial extracorporeal membrane oxygenation (13% vs 0%; P < 0.01). Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality (adjusted OR: 0.87 [95% CI: 0.49-1.55]; P = 0.64), bleeding (adjusted OR: 0.89 [95% CI: 0.49-1.62]; P = 0.70), stroke (adjusted OR: 0.74 [95% CI: 0.31-1.75]; P = 0.49), or major adverse cardiovascular and cerebrovascular events (adjusted OR 0.83 [95% CI: 0.50-1.35]; P = 0.44)., Conclusions: Spoke and hub patients experienced similar short-term outcomes within a regionalized CS network. The optimal strategy to promote standardized care and improved outcomes across regional CS networks merits further investigation., Competing Interests: Funding Support and Author Disclosures Dr Tehrani has served on the advisory board for Abbott; has received research grants from Boston Scientific and Inari Medical; and has served as a consultant for Boston Scientific. Dr Truesdell has served as a consultant for Abiomed. Dr Ibrahim has received honoraria from Medtronic. Dr Shah is supported by a National Institutes of Health K23 Career Development Award 1K23HL143179; has served as a consultant for Merck, Novartis, and Procyrion; and his institution has received grant support from Abbott, Roche, Merck and Bayer for unrelated research. Dr Batchelor has served as consultant for Boston Scientific, Abbott, Medtronic, and V-Wave. All other authors have reported that they have 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: Understanding trends in cardiovascular (CV) risk factors and CV disease according to age, sex, race, and ethnicity is important for policy planning and public health interventions., Objectives: The goal of this study was to project the number of people with CV risk factors and disease and further explore sex, race, and ethnical disparities., Methods: The prevalence of CV risk factors (diabetes mellitus, hypertension, dyslipidemia, and obesity) and CV disease (ischemic heart disease, heart failure, myocardial infarction, and stroke) according to age, sex, race, and ethnicity was estimated by using logistic regression models based on 2013-2018 National Health and Nutrition Examination Survey data and further combining them with 2020 U.S. Census projection counts for years 2025-2060., Results: By the year 2060, compared with the year 2025, the number of people with diabetes mellitus will increase by 39.3% (39.2 million [M] to 54.6M), hypertension by 27.2% (127.8M to 162.5M), dyslipidemia by 27.5% (98.6M to 125.7M), and obesity by 18.3% (106.3M to 125.7M). Concurrently, projected prevalence will similarly increase compared with 2025 for ischemic heart disease by 31.1% (21.9M to 28.7M), heart failure by 33.0% (9.7M to 12.9M), myocardial infarction by 30.1% (12.3M to 16.0M), and stroke by 34.3% (10.8M to 14.5M). Among White individuals, the prevalence of CV risk factors and disease is projected to decrease, whereas significant increases are projected in racial and ethnic minorities., Conclusions: Large future increases in CV risk factors and CV disease prevalence are projected, disproportionately affecting racial and ethnic minorities. Future health policies and public health efforts should take these results into account to provide quality, affordable, and accessible health care., Competing Interests: Funding Support and Author Disclosures Dr Mohebi is supported by the Barry Fellowship. Dr McCarthy is supported by a National. Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL094301-12). Dr Hyle is supported by the National Institute on Aging (R01 AG069575). Dr Januzzi is supported by the Hutter Family Professorship. Dr Ibrahim has received honoraria from Cytokinetics, Medtronic, Novartis, and Roche. Dr Gaggin has received research grant support from Roche Diagnostics, Jana Care, Ortho Clinical, Novartis, Pfizer, Alnylam, and Akcea; has received consulting income from Amgen, Eko, Merck, Roche Diagnostics, and Pfizer; has stock ownership for Eko; has received research payments for clinical endpoint committees from Radiometer; and has received research payment for clinical endpoint committees from the Baim Institute for Clinical Research for Abbott, Siemens, and Beckman Coulter. Dr Singer receives research support from Bristol Myers Squibb; and has received consulting income from Bristol Myers Squibb, Fitbit, Medtronic, and Pfizer. Dr Wasfy is supported by a grant from the American Heart Association (18 CDA 34110215); and has received consulting income from Pfizer and Biotronik. Dr Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. All other authors have reported that they have 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.)

Importance: Traditional models for predicting in-hospital mortality for patients with heart failure (HF) have used logistic regression and do not account for social determinants of health (SDOH)., Objective: To develop and validate novel machine learning (ML) models for HF mortality that incorporate SDOH., Design, Setting, and Participants: This retrospective study used the data from the Get With The Guidelines-Heart Failure (GWTG-HF) registry to identify HF hospitalizations between January 1, 2010, and December 31, 2020. The study included patients with acute decompensated HF who were hospitalized at the GWTG-HF participating centers during the study period. Data analysis was performed January 6, 2021, to April 26, 2022. External validation was performed in the hospitalization cohort from the Atherosclerosis Risk in Communities (ARIC) study between 2005 and 2014., Main Outcomes and Measures: Random forest-based ML approaches were used to develop race-specific and race-agnostic models for predicting in-hospital mortality. Performance was assessed using C index (discrimination), regression slopes for observed vs predicted mortality rates (calibration), and decision curves for prognostic utility., Results: The training data set included 123 634 hospitalized patients with HF who were enrolled in the GWTG-HF registry (mean [SD] age, 71 [13] years; 58 356 [47.2%] female individuals; 65 278 [52.8%] male individuals. Patients were analyzed in 2 categories: Black (23 453 [19.0%]) and non-Black (2121 [2.1%] Asian; 91 154 [91.0%] White, and 6906 [6.9%] other race and ethnicity). The ML models demonstrated excellent performance in the internal testing subset (n = 82 420) (C statistic, 0.81 for Black patients and 0.82 for non-Black patients) and in the real-world-like cohort with less than 50% missingness on covariates (n = 553 506; C statistic, 0.74 for Black patients and 0.75 for non-Black patients). In the external validation cohort (ARIC registry; n = 1205 Black patients and 2264 non-Black patients), ML models demonstrated high discrimination and adequate calibration (C statistic, 0.79 and 0.80, respectively). Furthermore, the performance of the ML models was superior to the traditional GWTG-HF risk score model (C index, 0.69 for both race groups) and other rederived logistic regression models using race as a covariate. The performance of the ML models was identical using the race-specific and race-agnostic approaches in the GWTG-HF and external validation cohorts. In the GWTG-HF cohort, the addition of zip code-level SDOH parameters to the ML model with clinical covariates only was associated with better discrimination, prognostic utility (assessed using decision curves), and model reclassification metrics in Black patients (net reclassification improvement, 0.22 [95% CI, 0.14-0.30]; P < .001) but not in non-Black patients., Conclusions and Relevance: ML models for HF mortality demonstrated superior performance to the traditional and rederived logistic regressions models using race as a covariate. The addition of SDOH parameters improved the prognostic utility of prediction models in Black patients but not non-Black patients in the GWTG-HF registry.

Background: Among patients with acute dyspnea, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 predict cardiovascular outcomes and death. Understanding the optimal means to interpret these elevated biomarkers in patients presenting with acute dyspnea remains unknown., Methods and Results: Concentrations of NT-proBNP, high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 were analyzed in 1448 patients presenting with acute dyspnea from the prospective, multicenter International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department (ICON-RELOADED) Study. Eight biogroups were derived based upon patterns in biomarker elevation at presentation and compared for differences in baseline characteristics. Of 441 patients with elevations in all 3 biomarkers, 218 (49.4%) were diagnosed with acute heart failure (HF). The frequency of acute HF diagnosis in this biogroup was higher than those with elevations in 2 biomarkers (18.8%, 44 of 234), 1 biomarker (3.8%, 10 of 260), or no elevated biomarkers (0.4%, 2 of 513). The absolute number of elevated biomarkers on admission was prognostic of the composite end point of mortality and HF rehospitalization. In adjusted models, patients with one, 2, and 3 elevated biomarkers had 3.74 (95% confidence interval [CI], 1.26-11.1, P = .017), 12.3 (95% CI, 4.60-32.9, P < .001), and 12.6 (95% CI, 4.54-35.0, P < .001) fold increased risk of 180-day mortality or HF rehospitalization., Conclusions: A multimarker panel of NT-proBNP, hsTnT, and IGBFP7 provides unique clinical, diagnostic, and prognostic information in patients presenting with acute dyspnea. Differences in the number of elevated biomarkers at presentation may allow for more efficient clinical risk stratification of short-term mortality and HF rehospitalization., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic underscored our healthcare system's unpreparedness to manage an unprecedented pandemic. Heart failure (HF) physicians from 14 different academic and private practice centers share their systems' challenges and innovations to care for patients with HF, heart transplantation, and patients on LVAD support during the COVID-19 pandemic. We discuss measures implemented to alleviate the fear in seeking care, ensure continued optimization of guideline directed medical therapy (GDMT), manage the heart transplant waiting list, continue essential outpatient monitoring of anticoagulation in LVAD patients and surveillance testing post-heart transplant, and prevent physician burnout. This collaborative work can build a foundation for better preparation in the face of future challenges., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: Current practice in cardiogenic shock is guided by expert opinion in guidelines and scientific statements from professional societies with limited high quality randomized trial data to inform optimal patient management. An international panel conducted a modified Delphi process with the intent of identifying aspects of cardiogenic shock care where there was uncertainty regarding optimal patient management., Methods: An 18-person multidisciplinary panel comprising international experts was convened. A modified RAND/University of California Los Angeles appropriateness methodology was used. A survey comprising 70 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9: 1 to 3 inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. A summary of the results was discussed as a group, and the survey was iterated and completed again before final analysis., Results: There was broad alignment with current international guidelines and consensus statements. Overall, 44 statements were rated as appropriate, 19 as uncertain, and 7 as inappropriate. There was no disagreement with a disagreement index <1 for all statements. Routine fluid administration was deemed to be inappropriate. Areas of uncertainty focused panel on pre-PCI interventions, the use of right heart catheterization to guide management, routine use of left ventricular unloading strategies, and markers of futility when considering escalation to mechanical circulatory support., Conclusions: While there was broad alignment with current guidance, an expert panel found several aspects of care where there was clinical equipoise, further highlighting the need for randomized controlled trials to better guide patient management and decision making in cardiogenic shock.

Background: Heart failure (HF) patients with CRT devices are a vulnerable patient population during the Coronavirus Disease 2019 (COVID-19) Pandemic. It is important to develop innovative virtual care models to deliver multidisciplinary care while minimizing the risk of SARS-CoV2 exposure., Objective: We aim to provide a description of how HF patients with CRT devices were assessed and managed in our virtual multidisciplinary clinic during the COVID-19 Pandemic. Clinical outcomes between this group of patients seen in virtual clinic and a historical cohort followed by in-person multi-disciplinary clinic prior to the pandemic were compared., Method: This is a retrospective cohort study of HF patients with CRT implants who were seen in the virtual multidisciplinary clinic from March 18th, 2020 to May 27th, 2020 (Virtual Visit Group, N = 43). A historical cohort of HF patients with CRT devices seen in the ReACT clinic in person during the same calendar time period in 2019 was used as a control group (In-Person Visit Group, N = 39). Both groups were followed until July 1st of the same calendar year (2020 or 2019) for clinical events. The primary outcome measure was a combined outcome of all-cause mortality and HF- or device-related hospitalizations during follow-up. The secondary outcome measures included patient satisfaction, COVID-19 infection, and other cardiovascular events., Results: In the Virtual-Visit Group, 21 patients (48.8%) had their initial ReACT clinic visit (first visit after CRT implant) as a virtual visit; 22 patients (51.2%) had prior in-person ReACT clinic visits before the first virtual visit. During the virtual visits, 12 patients had either potential cardiac symptoms or significant device interrogation findings that required clinical intervention. In post-virtual clinic patient satisfaction survey, all 22 patients surveyed (100%) reported being very satisfied or satisfied with the overall experience of the virtual clinic, and every patient (100%) said they would like to use telemedicine again. During a median follow-up period of 82 days (interquartile range [IQR] 61-96 days), one patient died from pneumonia of unclear etiology at an outside hospital, without documentation of COVID-19 positivity. No patient was hospitalized for HF- or arrhythmia-related complications. No patient was diagnosed with COVID-19. Compared with the In-Person Visit Group, there was no significant increase in mortality or major cardiovascular events in the Virtual-Visit Group (2.3% versus 5.1%, P = 0.60)., Conclusions and Relevance: Virtual multidisciplinary care was feasible for HF patients with cardiac resynchronization therapy devices and achieved good patient satisfaction. Virtual care was not associated with short-term increase in adverse events for HF patients with CRT device during the COVID-19 Pandemic. This virtual care model could help promote the adoption of digital health methodology for high-risk patients with multiple cardiac comorbidities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V.)

Background: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis., Methods: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls., Results: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level., Conclusions: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.)., (Copyright © 2021 Massachusetts Medical Society.)

Objectives: The aim of this study was to evaluate the combined impact of race, ethnicity, and sex on in-hospital outcomes using data from the National Inpatient Sample., Background: Cardiogenic shock (CS) is a major cause of mortality following ST-segment elevation myocardial infarction (STEMI). Early revascularization reduces mortality in such patients. Mechanical circulatory support (MCS) devices are increasingly used to hemodynamically support patients during revascularization. Little is known about racial, ethnic, and sex disparities in patients with STEMI and CS., Methods: The National Inpatient Sample was queried from January 2006 to September 2015 for hospitalizations with STEMI and CS. The associations between sex, race, ethnicity, and outcomes were examined using complex-samples multivariate logistic or generalized linear model regressions., Results: Of 159,339 patients with STEMI and CS, 57,839 (36.3%) were women. In-hospital mortality was higher for all women (range 40% to 45.4%) compared with men (range 30.4% to 34.7%). Women (adjusted odds ratio [aOR]: 1.11; 95% confidence interval [CI]: 1.06 to 1.16; p < 0.001) as well as Black (aOR: 1.18; 95% CI: 1.04 to 1.34; p = 0.011) and Hispanic (aOR: 1.19; 95% CI: 1.06 to 1.33; p = 0.003) men had higher odds of in-hospital mortality compared with White men, with Hispanic women having the highest odds of in-hospital mortality (aOR: 1.46; 95% CI: 1.26 to 1.70; p < 0.001). Women were older (age: 69.8 years vs. 63.2 years), had more comorbidities, and underwent fewer invasive cardiac procedures, including revascularization, right heart catheterization, and MCS., Conclusions: There are significant racial, ethnic, and sex differences in procedural utilization and clinical outcomes in patients with STEMI and CS. Women are less likely to undergo invasive cardiac procedures, including revascularization and MCS. Women as well as Black and Hispanic patients have a higher likelihood of death compared with White men., Competing Interests: FUNDING SUPPORT AND Author Disclosures Dr. Basir is a consultant for Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi, Procyrion, and Zoll. Dr. O’Neill is a consultant for Abiomed, Edwards Lifesciences, and Medtronic. 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.)

Objective: This study sought to determine whether patients with heart failure and reduced ejection fraction (HFrEF) with type 2 diabetes mellitus (T2DM) have similar reverse cardiac remodeling with sacubitril/valsartan as patients without T2DM., Background: Sacubitril/valsartan promotes reverse cardiac remodeling and improves outcomes in patients with HFrEF. Patients with HFrEF with T2DM have worse prognosis than those without T2DM., Methods: In this post hoc analysis of PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure), we examined changes in N-terminal pro-b-type natriuretic peptide (NT-proBNP), measures of cardiac remodeling, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores from baseline to 12 months following initiation of sacubitril/valsartan between patients with HFrEF with and without T2DM. Using latent growth curve modeling, we evaluated the longitudinal association between changes in NT-proBNP, left ventricular ejection fraction, and KCCQ-OS., Results: Among 794 patients enrolled, 361 (45.5%) had T2DM. NT-proBNP concentrations were modestly higher at baseline among patients with T2DM but were reduced after initiation of sacubitril/valsartan. Cross-sectional improvement was observed in left ventricular ejection fraction (T2DM: 28.3% at baseline and 37% at 12 months vs. non-T2DM: 28.1% at baseline and 38.3% at 12 months) and KCCQ-OS (T2DM: 71 at baseline and 83 at 12 months vs. non-T2DM: 76 at baseline and 88 at 12 months). Similar changes were also observed for other echocardiographic measures. In longitudinal analyses, the average NT-proBNP change was similar in patients with T2DM (-5.6% vs. -7.1% per 90-day interval; p = 0.64), whereas improvements in KCCQ-OS scores were slightly smaller (2.1 vs. 3.46 per 90-day interval; p = 0.07)., Conclusions: Sacubitril/valsartan favorably affects natriuretic peptide levels, reverse cardiac remodeling, and health status in patients with HFrEF with and without T2DM. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)., Competing Interests: Funding Support and Author Disclosures Dr. Felker has received personal fees from Novartis, Bristol Myers Squibb, Medtronic, Innolife, EBR Systems, Arena, Abbott, Alnylam, SC Pharma, Rocket, Sphingotec, LivaNova, Cardionomic, Relypsa, V-Wave, and MyoKardia; grants from the National Heart, Lung, and Blood Institute, American Heart Association, and Merck; and grants and personal fees from Amgen, Cytokinetics, and Roche Diagnostics. Dr. Piña has received consulting income from Relypsa and Novartis. Dr. Ibrahim is funded in part by the Dennis and Marilyn Barry Fund in Cardiovascular Research and has received honoraria from Novartis and Roche Diagnostics. Dr. Maisel has received consulting income from Abbott Vascular, Ortho Clinical Diagnostics, and Novartis. Drs. Prescott and Ward are employees of Novartis Pharmaceuticals Inc. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Respicardia, Sanofi Pasteur, and Theracos; and has consulted for Abbott, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, and Moderna. Dr. Januzzi reported receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Dr. Butler serves as a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, V-Wave Limited, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF)., Background: Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP., Methods: In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment., Results: Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both)., Conclusions: Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)., Competing Interests: Funding Support and Author disclosures This work was supported by Novartis Pharmaceuticals, Inc. Dr. Januzzi is supported in part by the Hutter Family Professorship. Dr. Prescott is an employee of Novartis Pharmaceuticals, Inc. Dr. Maisel has received consulting income from Abbott Vascular, Ortho Clinical Diagnostics, and Novartis. Dr. Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics and has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, and SC Pharma. Dr. Butler has received research support from the National Institutes of Health, Patient-Centered Outcomes Research Institute, and the European Union; and serves as a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Innolife, Janssen, LinaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, V-Wave Limited, and Vifor. Dr. Piña has received consulting income from Relypsa and Novartis. Dr. Ibrahim has received honoraria from Novartis Pharmaceuticals and Roche Diagnostics. Dr. Abbas is an employee of Novartis Pharmaceuticals, Inc. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institute of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr. Januzzi is a Trustee of the American College of Cardiology; has received grant support from Novartis Pharmaceuticals and Abbott Diagnostics and consulting income from Abbott Diagnostics, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Bayer, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Due to the complexity and chronicity of heart failure, engaging yet simple patient self-management tools are needed., Objective: This study aimed to assess the feasibility and patient engagement with a smartphone app designed for heart failure., Methods: Patients with heart failure were randomized to intervention (smartphone with the Habits Heart App installed and Bluetooth-linked scale) or control (paper education material) groups. All intervention group patients were interviewed and monitored closely for app feasibility while receiving standard of care heart failure management by cardiologists. The Atlanta Heart Failure Knowledge Test, a quality of life survey (Kansas City Cardiomyopathy Questionnaire), and weight were assessed at baseline and final visits., Results: Patients (N=28 patients; intervention: n=15; control: n=13) with heart failure (with reduced ejection fraction: 15/28, 54%; male: 20/28, 71%, female: 8/28, 29%; median age 63 years) were enrolled, and 82% of patients (N=23; intervention: 12/15, 80%; control: 11/13, 85%) completed both baseline and final visits (median follow up 60 days). In the intervention group, 2 out of the 12 patients who completed the study did not use the app after study onboarding due to illnesses and hospitalizations. Of the remaining 10 patients who used the app, 5 patients logged ≥1 interaction with the app per day on average, and 2 patients logged an interaction with the app every other day on average. The intervention group averaged 403 screen views (per patient) in 56 distinct sessions, 5-minute session durations, and 22 weight entries per patient. There was a direct correlation between duration of app use and improvement in heart failure knowledge (Atlanta Heart Failure Knowledge Test score; ρ=0.59, P=.04) and quality of life (Kansas City Cardiomyopathy Questionnaire score; ρ=0.63, P=.03). The correlation between app use and weight change was ρ=-0.40 (P=.19). Only 1 out of 11 patients in the control group retained education material by the follow-up visit., Conclusions: The Habits Heart App with a Bluetooth-linked scale is a feasible way to engage patients in heart failure management, and barriers to app engagement were identified. A larger multicenter study may be warranted to evaluate the effectiveness of the app., Trial Registration: ClinicalTrials.gov NCT03238729; http://clinicaltrials.gov/ct2/show/NCT03238729., (©Kevin S Wei, Nasrien E Ibrahim, Ashok A Kumar, Sidhant Jena, Veronica Chew, Michal Depa, Namrata Mayanil, Joseph C Kvedar, Hanna K Gaggin. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 20.01.2021.)

Background: Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes., Objectives: The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations., Methods: From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls., Results: The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p < 0.001), nearly identical to this dataset (1.08 points; p < 0.001)., Conclusions: Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)., Competing Interests: Author Disclosures The PROVE-HF Study was funded by Novartis Pharmaceuticals, Inc. Dr. Ibrahim is supported in part by the Dennis and Marilyn Barry Research Fund in Cardiology; and has received honoraria from Novartis and Roche Diagnostics. Dr. Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; and has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Rocket Pharma, and SC Pharma. Dr. Claggett has received consulting income from Amgen, Boehringer Ingelheim, Corvia, Myokardia, and Novartis. Dr. Desai has received research funding to his institution from AstraZeneca, Alnylam, Bayer, and Novartis; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Amgen, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Merck, Novartis, Relypsa, and Regeneron. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Drs. Prescott and Williamson are employees of Novartis Pharmaceuticals. Dr. Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from Applied Therapeutics, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a wage gap among men and women practicing cardiology. Differences in industry funding can be both a consequence of and a contributor to gender differences in salaries. We sought to determine whether gender differences exist in the distribution, types, and amounts of industry payments among men and women in cardiology., Methods: In this cross-sectional analysis, we used the Centers for Medicare & Medicaid Services Open Payment program database to obtain 2016 industry payment data for US cardiologists. We also used UK Disclosure data to obtain 2016 industry payments to UK cardiologists. Outcomes included the proportions of male and female cardiologists receiving industry funding and the mean industry payment amounts received by male and female cardiologists. Where possible, we also assessed 2014 and 2015 data in both locations., Results: Of the 22,848 practicing Centers for Medicare & Medicaid Services US cardiologists in 2016, 20,037 (88%) were men and 2,811 (12%) were women. Proportionally more men than women received industry payments in 2016 (78.0% vs 68.5%, respectively; P < .001). Men received higher overall mean industry payments than women ($6,193.25 vs. $2,501.55, P < .001). Results were similar in 2014 and 2015. Among UK cardiologists, more men (24.4%) than women (13.5%) received industry payments in 2016 (P < .001). However, although the difference in overall industry payments was numerically larger among men compared to women, this did not achieve statistical significance (£2,348.31 vs £1,501.37, respectively, P = .35)., Conclusions: Industry payments to cardiologists are common, and there are gender differences in these payments on both sides of the Atlantic., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: This study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration., Background: IGFBP7 is associated with impaired ventricular relaxation and worse prognosis., Methods: The ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained., Results: Among 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p < 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p < 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p < 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher log 2 -IGFBP7 concentrations in patients with acute HF predicted death or rehospitalization at 6 months (hazard ratio: 1.84 per log 2 -SD; 95% confidence interval: 1.30 to 2.61; p = 0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank: p < 0.001)., Conclusions: Among patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This study investigated the use of natriuretic peptides as inclusion criteria and to develop recommendations regarding their use. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are commonly used as inclusion criteria for heart failure (HF) clinical trials, but no consensus exists regarding their optimal use for this purpose. A comprehensive search of the Aggregate Analysis of ClincalTrials.gov database identified 3,446 HF trials. Of these, 365 recently completed or ongoing HF clinical trials (10.6%) used either BNP or NT-proBNP as inclusion criteria. A panel of experts discussed current practices and a path forward for the use of natriuretic peptides as inclusion criteria for HF trials. Significant variations existed across trials regarding which natriuretic peptide and which cutoff value were used. Overall, 43% used both natriuretic peptides, 33% used only NT-proBNP, and 24% used only BNP in determining eligibility. Studies using BNP and NT-proBNP concentrations as inclusion criteria had higher cardiovascular event rates and higher concentrations for study entry and were generally associated with higher event rates. Areas of uncertainty included use in certain patient populations in which natriuretic peptides are historically lower (e.g., black patients, obese patients, patients with HF with preserved ejection fraction) or higher (older patients, patients with atrial fibrillation). This paper discusses best practices regarding use of BNP or NT-proBNP in clinical trials and identification of gaps in medical literature, including importance of documentation in ClinicalTrials.gov studies to inform future research efforts., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Low donor heart availability underscores the need to identify all potentially transplantable organs. We sought to determine whether pre-emptive administration of pangenotypic direct-acting antiviral therapy can safely prevent the development of chronic hepatitis C virus (HCV) infection in uninfected recipients of HCV-infected donor hearts., Methods: Patients were recruited for this an open-label, single-centre, proof-of-concept study from Nov 1, 2017, to Nov 30, 2018. Following enrolment, the recipient's status on the heart transplantation waiting list was updated to reflect a willingness to accept either an HCV-positive or HCV-negative heart donor. Patients who underwent transplantation with a viraemic donor heart, as determined by nucleic acid testing (NAT), received pre-emptive oral glecaprevir-pibrentasvir before transport to the operating room followed by an 8-week course of glecaprevir-pibrentasvir after transplantation. Patients receiving HCV antibody-positive donor hearts without detectable circulating HCV RNA were followed using a reactive approach and started glecaprevir-pibrentasvir only if they developed viraemia. The primary outcome was achievement of sustained virological response 12 weeks after completion of glecaprevir-pibrentasvir therapy (SVR12). Patients were followed from study enrolment to 1 year after transplantation. This is an interim analysis, initiated after all enrolled patients reached the primary outcome. Results reflect data from Nov 1, 2017, to May 30, 2019. This trial is registered with ClinicalTrials.gov, number NCT03208244., Findings: 55 patients were assessed for eligibility and 52 consented to enrolment. 25 patients underwent heart transplantation with HCV-positive donor hearts (20 NAT-positive, five NAT-negative), three of whom underwent simultaneous heart-kidney transplantation. All 20 recipients of NAT-positive hearts tolerated glecaprevir-pibrentasvir and showed rapid viral suppression (median time to clearance 3·5 days, IQR 0·0-8·3), with the subsequent achievement of SVR12 by all 20. The five recipients of NAT-negative grafts did not become viraemic. Median pre-transplant waiting time for patients following enrolment in the HCV protocol was 20 days (IQR 8-57). Patient and allograft survival were 100% at a median follow-up of 10·7 months (range 6·5-18·0)., Interpretation: Pre-emptive administration of glecaprevir-pibrentasvir therapy results in expedited organ transplantation, rapid HCV suppression, prevention of chronic HCV infection, and excellent early allograft function in patients receiving HCV-infected donor hearts. Long-term outcomes are not yet known., Funding: American Association for the Study of Liver Diseases, National Institutes of Health, and the Massachusetts General Hospital., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Kidney injury is common in patients with cardiovascular disease., Objectives: We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications., Methods: One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR) <60 milliliters/minute/1.73 m 2 by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD., Results: During mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR <60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2·18, P = .01 and OR 1.54, 95% CI 1.10-2.15, P = .01, respectively) and non-procedural AKI (hazard ratio [HR] 1·49, 95% CI 1·24-1·78, P < .001 and HR 1.46, 95% CI 1.23-1.74, P < .001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, P = .001 and OR 2·02, 95% CI 1·35-3·03, P = .001, respectively)., Conclusions: In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident peri-procedural and non-procedural AKI, as well as progression to CKD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: High resting heart rate (HR ≥70 b.p.m.) is associated with worse clinical outcomes in heart failure with reduced ejection fraction (HFrEF). Heart rate, guideline-directed medical therapy (GDMT) with beta-blocker (BB), and cardiovascular outcomes were evaluated in a large integrated health network., Methods and Results: Using electronic health records we examined patients with chronic HFrEF (ejection fraction ≤35%) in sinus rhythm with at least 1 year of follow-up and available serial HR and medication data between 1 January 2000 and 31 December 2014. Among 6071 patients followed for median of 1330 days across 73 586 total visits, median HR remained stable over time with 61.2% of the follow-up period with HR  ≥70 b.p.m. At baseline, 27.9% of patients were on ≥ 50% GDMT target BB dose, 16.2% subjects at baseline, and 19.4% at the end of follow-up had HR ≥70 b.p.m. despite receiving ≥50% of target BB dose. In adjusted analyses, baseline HR was associated with all-cause mortality/heart failure (HF) hospitalization (hazard ratio 1.28 per 15 b.p.m. Heart rate increase; P < 0.001). In comparison, hazard ratio for BB dose was 0.97 (per 77.2 mg increase; P = 0.36). When evaluating patients based on HR and BB dose there was a significant difference in the cumulative hazard for all-cause mortality or HF hospitalization (P < 0.001). For HF hospitalization, hazard appeared to be more closely associated with HR rather than BB dose (P = 0.01)., Conclusion: In a real-world analysis, high resting HR was common in HFrEF patients and associated with adverse outcomes. Opportunities exist to improve GDMT and achieve HR control.

Objective: Severe aortic valve stenosis (AS) develops via insidious processes and can be challenging to correctly diagnose. We sought to develop a circulating biomarker panel to identify patients with severe AS., Methods: We enrolled study participants undergoing coronary or peripheral angiography for a variety of cardiovascular diseases at a single academic medical centre. A panel of 109 proteins were measured in blood obtained at the time of the procedure. Statistical learning methods were used to identify biomarkers and clinical parameters that associate with severe AS. A diagnostic model incorporating clinical and biomarker results was developed and evaluated using Monte Carlo cross-validation., Results: Of 1244 subjects (age 66.4±11.5  years, 28.7% female), 80 (6.4%) had severe AS (defined as aortic valve area (AVA) <1.0  cm 2 ). A final model included age, N-terminal pro-B-type natriuretic peptide, von Willebrand factor and fetuin-A. The model had good discrimination for severe AS (OR=5.9, 95% CI 3.5 to 10.1, p<0.001) with an area under the curve of 0.76 insample and 0.74 with cross-validation. A diagnostic score was generated. Higher prevalence of severe AS was noted in those with higher scores, such that 1.6% of those with a score of 1 had severe AS compared with 15.3% with a score of 5 (p<0.001), and score values were inversely correlated with AVA (r=-0.35; p<0.001). At optimal model cut-off, we found 76% sensitivity, 65% specificity, 13% positive predictive value and 98% negative predictive value., Conclusions: We describe a novel, multiple biomarker approach for diagnostic evaluation of severe AS., Trial Registration Number: NCT00842868., Competing Interests: Competing interests: SE receives institutional research support from Siemens and Boehringer Ingelheim Pharmaceuticals and consulting fees from Medtronic and Edwards Lifesciences. The remaining authors have no relationships to disclose. JLJ has received grant support from Abbott Diagnostics, Roche Diagnostics, Singulex and Prevencio; consulting income from Roche Diagnostics, Critical Diagnostics, Philips and Novartis; and participates in clinical endpoint committees/data safety monitoring boards for Novartis, Amgen, AbbVie, Pfizer, Janssen and Boehringer Ingelheim. CM is a consultant to Prevencio. RR and GB are employees of Prevencio. Siemens Diagnostics had no involvement in the present study design, collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.

Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost, morbidity, and mortality. Natriuretic peptide testing is now widely used to support diagnosis, prognostication, and management of patients with HF and are incorporated into HF clinical practice guidelines. Beyond the natriuretic peptides, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF and possibly to personalize care for those affected through better individual phenotyping. In this review, we will discuss natriuretic peptides and the more novel biomarkers by dividing them into categories based on the major pathophysiologic pathways they represent. Given the complex physiology in HF, it is reasonable to expect that the future of biomarker testing lies in the application of multimarker testing panels, precision medicine to improve HF care delivery, and the use of biomarkers in proteomics and metabolomics to further improve HF care.

Aims: Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions., Methods and Results: From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow-up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow-up, 177 (18%) developed new-onset HF. Independent predictors of new-onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino-terminal pro-B type natriuretic peptide and ST2). The c-statistic for the model without biomarkers was 0.69; including biomarkers increased the c-statistic to 0.76 (P < 0.001). A score was developed from the model. Patients in the highest score quintile had shortest time to incident HF compared with lower quintiles (log-rank P < 0.001). Following 100 bootstrap iterations, internal validation was confirmed with Harrell's c-statistic of 0.77. Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers at enrollment was associated with substantial attenuation of predictive value of the risk score., Conclusions: Patients undergoing coronary/peripheral angiographic procedures are a population at high risk for incident HF. We describe an accurate clinical and biomarker strategy for predicting incident HF and possibly intervening in such patients (NCT00842868)., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Purpose of Review: Biomarker-guided management of patients with chronic heart failure with reduced ejection fraction (HFrEF) remains controversial., Recent Findings: Biomarkers have established roles for diagnosis and prognostication in HF. Pilot data suggested that use of natriuretic peptides might be helpful to guide HF care. The recent Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) randomized-controlled trial did not find therapy guided by NT-proBNP to be more effective than usual care in improving the primary endpoint of HF hospitalization or cardiovascular mortality amongst patients with chronic HFrEF. Patients in GUIDE-IT received similar care and had similar NT-proBNP lowering regardless of treatment allocation. Though biomarkers retain important standing for diagnosis and prognosis in HF, the GUIDE-IT trial results suggest carefully managed patients may not benefit from a biomarker-guided strategy. Future studies focusing this intervention on patients treated in a more real-world setting are needed.

A single heart rate (HR) measurement may inform future prognosis in chronic heart failure with reduced ejection fraction (HFrEF). The importance of elevated HR across serial assessment is uncertain, particularly with well-applied guideline-directed medical therapy (GDMT) with beta blockers (BBs). In this post hoc analysis of 129 patients with chronic HFrEF in sinus rhythm, who had aggressive medication titration over 10.6 months, HR and BB use were assessed at each visit (average of 6 visits per patient). All-cause mortality was assessed. At baseline, 81 subjects (62.8%) had HR ≥70 beats/min; 40 subjects (31.0%) had high HR despite being on ≥50% of GDMT BB dose. At final visit, 30.4% of the subjects still had high HR despite achieving ≥50% target BB dose. There were no significant baseline differences in demographics or BB doses in patients with HR <70 vs HR ≥70 beats/min. In adjusted model in which HR was treated as time-dependent covariate, an increase in HR of 10  beats/min was associated with an increased hazard of all-cause mortality during follow-up (adjusted hazard ratio per 10 beats/min = 2.46; 95% confidence interval 1.46-4.16, p <0.001). In conclusion, in well-managed patients with HFrEF, high HR was frequent even after aggressive medication titration, and often despite being on at least 50% of GDMT BB dose. An increase in HR was associated with worse clinical outcomes (Clinicaltrials.gov NCT#00351390)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We sought to develop a multiple biomarker approach for prediction of incident major adverse cardiac events (MACE; composite of cardiovascular death, myocardial infarction, and stroke) in patients referred for coronary angiography. In a 649-participant training cohort, predictors of MACE within 1 year were identified using least-angle regression; over 50 clinical variables and 109 biomarkers were analyzed. Predictive models were generated using least absolute shrinkage and selection operator with logistic regression. A score derived from the final model was developed and evaluated with a 278-patient validation set during a median of 3.6 years follow-up. The scoring system consisted of N-terminal pro B-type natriuretic peptide (NT-proBNP), kidney injury molecule-1, osteopontin, and tissue inhibitor of metalloproteinase-1; no clinical variables were retained in the predictive model. In the validation cohort, each biomarker improved model discrimination or calibration for MACE; the final model had an area under the curve (AUC) of 0.79 (p <0.001), higher than AUC for clinical variables alone (0.75). In net reclassification improvement analyses, addition of other markers to NT-proBNP resulted in significant improvement (net reclassification improvement 0.45; p = 0.008). At the optimal score cutoff, we found 64% sensitivity, 76% specificity, 28% positive predictive value, and 93% negative predictive value for 1-year MACE. Time-to-first MACE was shorter in those with an elevated score (p <0.001); such risk extended to at least to 4 years. In conclusion, in a cohort of patients who underwent coronary angiography, we describe a novel multiple biomarker score for incident MACE within 1 year (NCT00842868)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To assess prognostic meaning of worsening renal failure (WRF) occurring during management of chronic heart failure (HF) with reduced ejection fraction., Background: When WRF develops during titration of HF medical therapy, it commonly leads to less aggressive care., Methods: A total of 151 patients enrolled in a prospective, randomized study of standard of care (SOC) HF therapy versus SOC plus a goal N-terminal pro-B type natriuretic peptide (NT-proBNP) < 1000 pg/mL were examined. Cardiovascular (CV) event (defined as worsening HF, hospitalization for HF, significant ventricular arrhythmia, acute coronary or cerebral ischemia, or CV death) at 1 year relative to WRF (defined as any reduction in estimated glomerular filtration rate) 90 days postenrollment were tabulated., Results: Those developing WRF by 3 months had an average 14% reduction in estimated glomerular filtration rate. There was no difference in incidence of WRF between study arms (43% in SOC, 57% in NT-proBNP, P = .29). During the first 3 months of therapy titration, incident WRF was associated with numerically fewer CV events at 1 year compared with those without WRF (mean 0.81 vs 1.16 events, P = .21). WRF was associated trend toward fewer CV events in the SOC arm (hazard ratio 0.45, 95% confidence interval 0.16-1.24, P = .12); the NT-proBNP-guided arm had numerically lower CV event rates regardless of WRF. Subjects with NT-proBNP <1000 pg/mL and WRF received higher doses of guideline directed medical therapies, lower doses of loop diuretics, and had significantly lower CV event rates (P < .001)., Conclusions: Modest degrees of WRF are common during aggressive HF with reduced ejection fraction management, but we found no significant association with CV outcomes. HF care guided by NT-proBNP was not associated with more WRF compared with SOC, and led to benefit regardless of final renal function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to define and assess the significance of worsening heart failure (WHF) in patients with chronic ambulatory heart failure with reduced ejection fraction (HFrEF)., Background: WHF has been identified as a potentially relevant clinical event in patients with acute heart failure (HF) and is increasingly used as an endpoint in clinical trials. No standardized definition of WHF exists. It remains uncertain how WHF relates to risk for other HF events or how treatment may affect WHF., Methods: A total of 151 symptomatic patients with chronic HFrEF were randomized to standard of care HF management or a goal to lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations ≤1,000 pg/ml in addition to standard of care. WHF was prospectively defined as: 1) new or progressive symptoms and/or signs of decompensated HF; and 2) unplanned intensification of diuretic therapy., Results: Over a mean follow-up of 10 months, 45 subjects developed WHF. At baseline, patients developing incident WHF had higher ejection fraction (31% vs. 25%; p = 0.03), were more likely to have jugular venous distension and edema (p < 0.02), were less likely to receive angiotensin-converting enzyme inhibitors or received these agents at lower doses (p < 0.04), and also received higher loop diuretic doses (p < 0.001). Occurrence of WHF was strongly associated with subsequent HF hospitalization/cardiovascular death (hazard ratio, landmark analysis: 18.8; 95% confidence interval: 5.7 to 62.5; p < 0.001). NT-proBNP-guided care reduced the incidence of WHF in adjusted analyses (hazard ratio: 0.52; p = 0.06) and improved event-free survival (log-rank test p = 0.04)., Conclusions: In chronic HFrEF, WHF was associated with substantial risk for morbidity and mortality. NT-proBNP-guided care reduced risk for WHF., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)