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Abstract Inadequate at-home management and self-awareness of heart failure (HF) exacerbations are known to be leading causes of the greater than 1 million estimated HF-related hospitalizations in the USA alone. Most current at-home HF management protocols include paper guidelines or exploratory health applications that lack rigor and validation at the level of the individual patient. We report on a novel triage methodology that uses machine learning predictions for real-time detection and assessment of exacerbations. Medical specialist opinions on statistically and clinically comprehensive, simulated patient cases were used to train and validate prediction algorithms. Model performance was assessed by comparison to physician panel consensus in a representative, out-of-sample validation set of 100 vignettes. Algorithm prediction accuracy and safety indicators surpassed all individual specialists in identifying consensus opinion on existence/severity of exacerbations and appropriate treatment response. The algorithms also scored the highest sensitivity, specificity, and PPV when assessing the need for emergency care. Lay summary Here we develop a machine-learning approach for providing real-time decision support to adults diagnosed with congestive heart failure. The algorithm achieves higher exacerbation and triage classification performance than any individual physician when compared to physician consensus opinion. Graphical abstract

The TOPCAT trial investigated spironolactone vs placebo in patients with heart failure with preserved ejection fraction (HFpEF). Although the primary endpoint was not statistically significant, treatment with spironolactone did reduce heart failure hospitalizations compared with placebo. TOPCAT's impact on prescribing patterns in the United States is not well-characterized. We performed a retrospective analysis of discharge prescribing data in the Get With The Guidelines-Heart Failure Registry among patients with left ventricular ejection fraction ≥50% discharged between January 2009 and December 2016 to assess prescribing trends upon dissemination of TOPCAT results. Of 142,201 patients included in the study, 18,581 (13.1%) were prescribed mineralocorticoid receptor antagonists (MRAs) at discharge. Compared with those not prescribed MRAs, patients discharged on MRAs were generally younger (75 vs 78 years), and report white race (76.7% vs 72.0%), more likely to have had prior heart failure hospitalizations (75.5% vs 65.7%), lower brain natriuretic peptide levels (492 vs 545 pg/mL), but similar serum creatinine levels (1.2 vs 1.2 mg/dL) upon admission. MRA prescribing modestly increased over time (p

Objective To identify temporal trends in the use of exercise treadmill testing (ETT) and cardiorespiratory fitness (CRF) estimated by ETT in metabolic equivalents (METs). Patients and methods We compiled an ETT database of all available treadmill tests—including those with concomitant stress echocardiography and nuclear perfusion imaging studies—performed at Duke University Hospital from January 1, 1970- December 31, 2012. Six different ramp protocols were used in these combined modalities. CRF at maximal exertion was estimated using established metrics. Eligible patients were required to have no missing data on maximal treadmill speed, grade, and protocol. Results The most commonly used ETT protocol was the Bruce (n = 28,877), followed by manual test (n = 7390). Since the 1980’s, the use of ETT for clinical purposes declined substantially; there was a decreased trend in utilization of 9.4% over the decades 1990–1999 and 2000–2009. When standard protocol (Bruce) was assessed in isolation, trends in CRF decreased progressively from 1970 to 2012 (mean METs (standard deviation): 11.7 (4.3) to 10.5 (3.5)). After adjusting for baseline comorbidities, the trend was reduced to a lesser degree. Conclusions The use of ETT at our institution has declined over time, perhaps due to changes in clinical practice. In patients undergoing ETT using the standard Bruce protocol, CRF decreased progressively over the last five decades. Future studies are needed to clarify the etiology of the decrease in use of such a powerful predictor of clinical outcomes in our medical care environment.

Background Limited data exist to guide treatment for patients with heart failure with preserved ejection fraction and atrial fibrillation, including the important decision regarding rate versus rhythm control. Methods and Results We analyzed the Get With The Guidelines—Heart Failure (GWTG‐HF) registry linked to Medicare claims data from 2008 to 2014 to describe current treatments for rate versus rhythm control and subsequent outcomes in patients with heart failure with preserved ejection fraction and atrial fibrillation using inverse probability weighted analysis. Rhythm control was defined as use of an antiarrhythmic medication, cardioversion, or AF ablation or surgery. Rate control was defined as use of any combination of β‐blocker, calcium channel blocker, and digoxin without evidence of rhythm control. Among 15 682 fee‐for‐service Medicare patients, at the time of discharge, 1857 were treated with rhythm control and 13 825 with rate control, with minimal differences in baseline characteristics between groups. There was higher all‐cause death at 1 year in the rate control compared with the rhythm control group (37.5% and 30.8%, respectively, P CI , 0.75–0.98; P =0.02). Conclusions Rhythm control in patients aged 65 and older with heart failure with preserved ejection fraction and AF was associated with a lower risk of 1 year all‐cause mortality. Future prospective randomized studies are needed to explore this potential benefit.

AIMS: Cardiorespiratory fitness (CRF) is closely linked to health status and clinical outcomes in heart failure (HF) patients. We aimed to test whether biomarkers can reflect CRF and its change over time. METHODS AND RESULTS: This post-hoc analysis utilized data from ambulatory cohorts of heart failure with reduced ejection fraction (HFrEF) (IRONOUT) and heart failure with preserved ejection fraction (HFpEF) (RELAX). Cardiopulmonary exercise testing, 6 minute walk distance (6MWD), and serum biomarkers were measured at baseline and 16 or 24 week follow-up (for IRONOUT and RELAX respectively). Biomarkers included N-terminal pro–B-type natriuretic peptide (NT-proBNP), soluble ST2, growth differentiation factor-15 (GDF-15), and galectin-3. Analysis included 225 patients with HFrEF and 216 with HFpEF. Baseline peak VO(2), VE/VCO(2) slope and 6MWD showed a mild correlation with the doubling of all four tested biomarkers in HFrEF and HFpEF. Following multivariable adjustment (including all biomarkers), the only significant association between change in biomarker and functional parameter in HFrEF was change in NT-proBNP and change in VE/VCO(2) slope (3.596% increase per doubling, 95%CI [0.779, 6.492]; p=0.012). In HFpEF a decrease in peak VO(2) was associated with an increase in NT-proBNP (−0.726 ml/min/kg per doubling, 95%CI [−1.100, −0.353]; p

BACKGROUND Evidence suggests that systemic inflammation may adversely impact HDL function. In this study we sought to evaluate the independent and incremental predictive performance of GlycA—a novel serum inflammatory biomarker that is an aggregate measure of enzymatically glycosylated acute phase proteins—and HDL subclasses on adverse events in a retrospective observational study of a secondary prevention population and to understand a priori defined potential interactions between GlycA and HDL subclasses. METHODS GlycA and HDL subclasses were measured using proton nuclear magnetic resonance spectroscopy in 7617 individuals in the CATHGEN (CATHeterization GENetics) cardiac catheterization biorepository. RESULTS GlycA was associated with presence [odds ratio (OR) 1.07 (1.02–1.13), P = 0.01] and extent [OR 1.08 (1.03, 1.12) P < 0.0005] of coronary artery disease and with all-cause mortality [hazard ratio (HR) 1.34 (1.29–1.39), P < 0.0001], cardiovascular mortality [1.37 (1.30–1.45), P < 0.0001] and noncardiovascular mortality [1.46 (1.39–1.54) P < 0.0001] in models adjusted for 10 cardiovascular risk factors. GlycA and smaller HDL subclasses had independent but opposite effects on mortality risk prediction, with smaller HDL subclasses being protective [HR 0.69 (0.66–0.72), P < 0.0001]. There was an interaction between GlycA and smaller HDL subclasses—increasing GlycA concentrations attenuated the inverse association of smaller HDL subclasses with mortality. Adding GlycA and smaller HDL subclasses into the GRACE (Global Registry of Acute Coronary Events) and Framingham Heart Study Risk Scores improved mortality risk prediction, discrimination and reclassification. CONCLUSIONS These findings highlight the interaction of systemic inflammation and HDL with clinical outcomes and may increase precision for clinical risk assessment in secondary prevention populations.

The purpose of this study was to evaluate the association of physical activity (PA) level and longitudinal PA trajectory with a composite heart failure hospitalization and mortality endpoint over a 5-year follow-up period following implantation.Low device measured PA early after implantation of an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) is associated with poor outcomes.We linked daily PA data from the Boston Scientific ALTITUDE dataset of patients with ICD or CRT-D implantation to Medicare claims data. We used a joint model to investigate the association of the composite endpoint with 1) the time-varying point estimate of PA and 2) the time-varying trajectory/slope of PA during follow-up.Among 20,927 patients with median activity level 85 min/day, 14.1% and 49.6% experienced the composite endpoint at 1 and 5 years. Adjusted joint model results showed that there was a 1.13 (95% confidence interval: 1.12 to 1.13)-fold increase in the hazard of the composite endpoint for 75 min of daily PA relative to 85 min of PA; and a within-patient 10-min decrease in average daily PA over an 8-week period from 85 to 75 min was associated with a hazard ratio of 4.02 (95% confidence interval: 3.82 to 4.22) for the composite endpoint.Patients with large decreases in PA have significantly higher risk of experiencing heart failure hospitalization or death. PA data from implantable devices may identify patients before clinical decompensation.

Objectives The aim of this study was to assess for a treatment interaction between statin use and exercise training (ET) response. Background Recent data suggest that statins may attenuate ET response, but limited data exist in patients with heart failure (HF). Methods HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized trial of 2,331 patients with chronic HF with ejection fraction ≤35% who were randomized to usual care with or without ET. We evaluated whether there was a treatment interaction between statins and ET response for the change in quality of life and aerobic capacity (peak oxygen consumption and 6-min walk distance) from baseline to 3 months. We also assessed for a treatment interaction among atorvastatin, simvastatin, and pravastatin and change in these endpoints with ET. Multiple linear regression analyses were performed for each endpoint, adjusting for baseline covariates. Results Of 2,331 patients in the HF-ACTION trial, 1,353 (58%) were prescribed statins at baseline. Patients treated with statins were more likely to be older men with ischemic HF etiology but had similar use of renin angiotensin system blockers and beta-blockers. There was no evidence of a treatment interaction between statin use and ET on changes in quality of life or exercise capacity, nor was there evidence of differential association between statin type and ET response for these endpoints (all p values >0.05). Conclusions In a large chronic HF cohort, there was no evidence of a treatment interaction between statin use and short-term change in aerobic capacity and quality of life with ET. These findings contrast with recent reports of an attenuation in ET response with statins in a different population, highlighting the need for future prospective studies. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)

Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.

Metabolic impairment is an intrinsic component of heart failure (HF) pathophysiology. Although initially conceived as a myocardial defect, metabolic dysfunction is now recognized as a systemic process with complex interplay between the myocardium and peripheral tissues and organs. Specifically, HF-associated metabolic dysfunction includes alterations in substrate utilization, insulin resistance, defects in energy production, and imbalanced anabolic-catabolic signaling leading to cachexia. Each of these metabolic abnormalities is associated with significant morbidity and mortality in patients with HF; however, their detection and therapeutic management remains challenging. Given the difficulty in obtaining human cardiac tissue for research purposes, peripheral blood metabolomic profiling, a well-established approach for characterizing small-molecule metabolite intermediates from canonical biochemical pathways, may be a useful technology for dissecting biomarkers and mechanisms of metabolic impairment in HF. In this review, metabolic abnormalities in HF will be discussed with particular emphasis on the application of metabolomic profiling to detecting, risk stratifying, and identifying novel targets for metabolic therapy in this heterogeneous population.

Background Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers associated with these changes remain unclear. Objectives This study sought to describe the metabolomic profiles of patients along the spectrum of systolic HF, determine their association with adverse outcomes in a clinical trial of HF, and evaluate whether identified metabolites change with treatment for end-stage systolic HF. Methods To assess association of metabolites with clinical outcomes, we evaluated a population of 453 chronic systolic HF patients who had been randomized to exercise training versus usual care. To assess change in metabolites with mechanical circulatory support, 41 patients with end-stage HF who underwent left ventricular assist device (LVAD) placement were studied. Targeted, quantitative profiling of 60 metabolites using tandem flow injection mass spectrometry was performed on frozen plasma samples obtained prior to randomization, as well as prior to and ≥90 days post-placement in the LVAD group. Principal components analysis was used for data reduction. Results Five principal components analysis–derived factors were significantly associated with peak V o 2 levels at baseline in fully adjusted models. Of these, factor 5 (composed of long-chain acylcarnitines) was associated with increased risk of all 3 pre-specified clinical trial outcomes: all-cause mortality/all-cause hospitalization, all cause-hospitalization, and cardiovascular death or cardiovascular hospitalization. Individual components of factor 5 were significantly higher in patients with end-stage HF prior to LVAD placement and decreased significantly post-implantation. Conclusions In chronic HF patients, circulating long-chain acylcarnitine metabolite levels were independently associated with adverse clinical outcomes and decreased after long-term mechanical circulatory support. These metabolites may serve as potential targets for new diagnostics or therapeutic interventions. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )

Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF).The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility.Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events.Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds.In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology.

Background: There are limited treatment options for patients with HFpEF, with guidelines focusing on diuresis and management of associated cardiovascular conditions. In the TOPCAT trial, treatment with spironolactone in patients with HFpEF compared to placebo did not significantly decrease the incidence of the composite primary outcome, but the incidence of heart failure (HF) hospitalization was significantly lower. The impact of the TOPCAT results on mineralocorticoid antagonists (MRA) prescribing rates is unknown. We analyzed discharge prescribing rates of MRAs in the Get With The Guidelines-Heart Failure (GWTG-HF) registry to assess for practice changes following dissemination of TOPCAT results in 2013. Methods: All patients recorded in GWTG-HF with LVEF ≥ 50% and discharged between January 2009 and December 2016 were included in the study. Data were summarized by calendar year quarters (Q). The TOPCAT trial results were first presented in November 2013, so patients were dichotomized into those discharged before TOPCAT (2009Q1 through 2013Q3) and those after TOPCAT (2013Q4 through 2016Q4). Discharge prescribing rates for MRAs, beta blockers, ACE inhibitors, and ARBs were assessed for overall trends and change in prescribing rates after 2013Q3 by segmented regression. Results: Of 142,201 HFpEF patients included in the study, 18,581 (13.1%) were prescribed a MRA at discharge. Throughout the study period, MRA prescribing steadily increased (2009Q1 = 11.3%; 2016Q4 = 14.8%), without significant change in overall trend following announcement of TOPCAT results (p=0.17) (Figure 1). Discharge prescribing rates were largely stable for beta blockers but with a statistically significant change in trend after TOPCAT (2009Q1 = 82.8%; 2016Q4 = 80.5%; p < 0.0001), while prescribing rates for ACE/ARB decreased significantly throughout the study period without change in trend following TOPCAT (2009Q1 = 74.7%; 2016Q4 = 53.7%; p = 0.58). Conclusions: The prescribing rates for MRAs in HFpEF at hospital discharge modestly increased over time, with little discernible influence of TOPCAT. These findings suggest there has been gradual, modest MRA adoption in the absence of other therapeutic options and highlight the need for further trials on the efficacy and safety of MRAs in HFpEF.

Background Perceived risks of hyperkalemia and acute renal insufficiency may limit use of mineralocorticoid receptor antagonist ( MRA ) therapy in patients with heart failure, especially those with diabetes mellitus or chronic kidney disease. Methods and Results Using clinical registry data linked to Medicare claims, we analyzed patients hospitalized with heart failure between 2005 and 2013 with a history of diabetes mellitus or chronic kidney disease. We stratified patients by MRA use at discharge. We used inverse probability–weighted proportional hazards models to assess associations between MRA therapy and 30‐day, 1‐year, and 3‐year mortality, all‐cause readmission, and readmission for heart failure, hyperkalemia, and acute renal insufficiency. We performed interaction analyses for differential effects on 3‐year outcomes for reduced, borderline, and preserved ejection fraction. Of 16 848 patients, 12.3% received MRA therapy at discharge. Higher serum creatinine was associated with lower odds of MRA use (odds ratio, 0.66; 95% confidence interval, 0.61–0.71); serum potassium was not (odds ratio, 1.00; 95% confidence interval, 0.90–1.11). There was no mortality difference between groups. MRA therapy was associated with greater risks of readmission for hyperkalemia and acute renal insufficiency and lower risks of long‐term all‐cause readmission. Patients on MRA therapy with borderline or preserved ejection fraction had greater risks of readmission for hyperkalemia ( P =0.02) and acute renal insufficiency ( P Conclusions Among patients with heart failure and diabetes mellitus or chronic kidney disease, MRA use was associated with lower risk of all‐cause readmission despite greater risk of hyperkalemia and acute renal insufficiency.

Conflicting data exist regarding the associations of early repolarization (ER) with electrocardiogram (ECG) and clinical outcomes in blacks. We examined the association of ER defined by J point elevation (JPE) and all-cause mortality, and heart failure (HF) hospitalization in blacks in the Jackson Heart Study (JHS) cohort. We included JHS participants with ECGs from the baseline visit coding JPE and excluded participants with paced rhythms or QRS duration ≥120 ms. We compared the cumulative incidence of 10-year all-cause mortality and 8-year HF hospitalization by presence of JPE ≥0.1 mV in any ECG lead at baseline using Kaplan-Meier estimates and multivariable Cox models. Of the 4,978 participants, 1,410 (28%) had JPE at baseline: anterior leads 97.8%, lateral leads 8.3%, and inferior leads 2.9%. Compared with participants without JPE, those with JPE were younger, more likely to be male and current smokers, and less likely to have hypertension. Over a median follow-up of 8 years, there were no significant differences in the cumulative incidence or multivariable-adjusted hazards of all-cause mortality or HF hospitalization in participants with and without JPE in any lead (adjusted hazard ratio 0.97, 95% confidence interval 0.89 to 1.52, and adjusted hazard ratio 1.18, 95% confidence interval 0.9 to 1.54, respectively). Of the 2,523 participants who completed Exam 3 without JPE at baseline, 246 (10%) developed JPE over follow-up. In conclusion, JPE on ECG was not associated with long-term mortality or HF hospitalization in a large prospective black community cohort, suggesting that ER may represent a benign ECG finding in blacks.

Recent clinical trials in patients with heart failure with preserved ejection fraction (HFpEF) have provided important insights into participant selection strategies. Historically, HFpEF trials have included patients with relatively preserved left ventricular ejection fraction ranging from 40% to 55% and a clinical history of heart failure. Contemporary HFpEF trials have also incorporated inclusion criteria such as hospitalization for HFpEF, altered functional capacity, cardiac structural and functional abnormalities, and abnormalities in neurohormonal status (e.g., elevated natriuretic peptide levels). Careful analyses of the effect of these patient selection criteria on outcomes in prior trials provide valuable lessons for future trial design. We review recent and ongoing HFpEF clinical trials from a patient selection perspective and appraise trial patient selection methodologies in relation to outcomes. This review reflects discussions between clinicians, scientists, trialists, regulators, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum in Paris, France, on December 6, 2013. (C) 2015 by the American College of Cardiology Foundation.

Clinical trials of therapeutic agents for heart failure with preserved ejection fraction (HFpEF) have yielded little beyond disappointment for physicians caring for these ubiquitous patients who comprise over one-half of the annual 1,000,000 heart failure (HF) discharges in the United States [(1)][1

The discovery and use of diuretics are ancient history. Paleolithic humans may have discovered the original diuretic when they found caffeine-containing plants whose seeds and bark were used to prepare beverages [(1)][1]. In the 16th century, the renowned physician Paracelsus identified mercurous

Background— Daily physical activity assessed by accelerometers represents a novel method to assess the impact of interventions on heart failure (HF) patients’ functional status. We hypothesized that daily activity varies by patient characteristics and correlates with established measures of HF severity in HF with preserved ejection fraction. Methods and Results— In this ancillary study of the NEAT-HFpEF trial (Nitrate’s Effects on Activity Tolerance in HF With Preserved Ejection Fraction), average daily accelerometer units (ADAU) and hours active per day were assessed during a 14-day period before starting isosorbide mononitrate or placebo (n=110). Baseline ADAU was negatively associated with age, female sex, height, and body mass index, and these variables accounted for 28% of the variability in ADAU ( P P Conclusions— Daily activity is a measure of HF-related and global functional status in HF with preserved ejection fraction. As compared with intermittently assessed standard HF assessments, change in daily activity may provide unique information about the impact of HF interventions on functional status. Clinical Trial Registration— URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02053493

V. Pettilä on työryhmän ARISE Investigators jäsen. Study objective: The influence of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) on the conduct of future sepsis research is unknown. We seek to examine the potential effect of the new definitions on the identification and outcomes of patients enrolled in a sepsis trial. Methods: This was a post hoc analysis of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial of early goal-directed therapy that recruited 1,591 adult patients presenting to the emergency department (ED) with early septic shock diagnosed by greater than or equal to 2 systemic inflammatory response syndrome criteria and either refractory hypotension or hyperlactatemia. The proportion of participants who would have met the Sepsis-3 criteria for quick Sequential Organ Failure Assessment (qS0FA) score, sepsis (an increased Sequential Organ Failure Assessment score >= 2 because of infection) and septic shock before randomization, their baseline characteristics, interventions delivered, and mortality were determined. Results: There were 1,139 participants who had a qSOFA score of greater than or equal to 2 at baseline (71.6% [95% confidence interval [Cl) 69.4% to 73.8%]). In contrast, 1,347 participants (84.7% [95% CI 82.9% to 86.4%]) met the Sepsis-3 criteria for sepsis. Only 1,010 participants were both qSOFA positive and met the Sepsis-3 criteria for sepsis (63.5% [95% CI 61.1% to 65.8%]). The Sepsis-3 definition for septic shock was met at baseline by 203 participants (12.8% [95% CI 11.2% to 14.5%]), of whom 175 (86.2% [95% CI 81.5% to 91.0%]) were also qSOFA positive. Ninety-day mortality for participants fulfilling the Sepsis-3 criteria for sepsis and septic shock was 20.4% (95% CI 18.2% to 22.5%) (274/1,344) and 29.6% (95% CI 23.3% to 35.8% [60/203]) versus 9.4% (95% CI 5.8% to 13.1%) (23/244) and 17.1% (95% CI 15.1% to 19.1% [237/1,388]), respectively, for participants not meeting the criteria (risk differences 11.0% [95% CI 6.2% to 14.8%] and 12.5% [95% CI 6.3% to 19.4%], respectively). Conclusion: Most ARISE participants did not meet the Sepsis-3 definition for septic shock at baseline. However, the majority fulfilled the new sepsis definition and mortality was higher than for participants not fulfilling the criteria. A quarter of participants meeting the new sepsis definition did not fulfill the qSOFA screening criteria, potentially limiting its utility as a screening tool for sepsis trials with patients with suspected infection in the ED. The implications of the new definitions for patients not eligible for recruitment into the ARISE trial are unknown.

For the 2015 American College of Cardiology Scientific Sessions in San Diego, California, several Duke Cardiology fellows decided to try something different. Instead of staying in private hotel rooms, we rented a house in Old Town San Diego where we stayed together in a family-style atmosphere. We

Background Metabolic impairment is an important contributor to heart failure ( HF ) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction ( HF p EF ). We sought to determine metabolic abnormalities in HF p EF and identify pathways differentially altered in HF p EF versus HF with reduced ejection fraction ( HF r EF ). Methods and Results We identified HF p EF cases, HF r EF controls, and no‐ HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HF p EF cases (N=282) were defined by left ventricular ejection fraction ( LVEF ) ≥45%, diastolic dysfunction grade ≥1, and history of HF ; HF r EF controls (N=279) were defined similarly, except for having LVEF HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA . In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups ( P< 0.0001) and were greater in HF r EF than HF p EF ( P =0.0004), both of which were greater than no‐ HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. Conclusions We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HF p EF and HF r EF . These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

Background— In-hospital worsening heart failure (WHF) is an important event that has inconsistent definitions used across trials. We used data from 2 acute heart failure (HF) trials from the National Institutes of Health HF Network, DOSE (Diuretic Optimization Strategies Evaluation) and ROSE (Renal Optimization Strategies), to understand event rates associated with different WHF definitions. Methods and Results— We pooled data from 668 patients in DOSE and ROSE and assessed the relationship between WHF and the composite end point of rehospitalization, emergency room visits for HF, and mortality through 60 days. We also assessed for a differential relationship between the timing of WHF development and outcomes. The overall incidence of WHF was 14.6% (24.1% in DOSE, 6.3% in ROSE, and 5.0% in DOSE using the ROSE definition). WHF was associated with an increase in the composite end point (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11–2.42; P =0.01). However, the association between WHF and outcomes was significantly stronger in ROSE than in DOSE (HR, 2.67; 95% CI, 1.45–4.91; P P =0.31, respectively). Development of WHF between baseline to 24 hours compared with 24 to 48 hours or 48 to 72 hours demonstrated a trend toward improved outcomes (HR, 0.49; 95% CI, 0.21–1.17; P =0.11 and HR, 0.45; 95% CI, 0.20–1.04; P =0.06, respectively). Conclusions— A WHF definition that excluded the intensification of diuretics resulted in a lower event rate but a stronger association with outcomes. These data support the need for continued efforts to standardize WHF definitions in clinical trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00577135 (DOSE) and NCT01132846 (ROSE).

Cardiac rehabilitation (CR) is a proven therapy for patients with heart failure (HF) that improves exercise capacity and quality of life [(1)][1]. The most recent guidelines recommend exercise training and CR as class I and class IIa recommendations [(2)][2]. In February 2014, the Centers for

There are limited data describing outcomes associated with an elevated heart rate in patients with heart failure with reduced ejection fraction (HFrEF) in routine clinical practice. We identified patients with HFrEF at Duke University Hospital undergoing echocardiograms and heart rate assessments without paced rhythms or atrial fibrillation. Outcomes (all-cause mortality or hospitalization and medical costs per day alive) were assessed using electronic medical records, hospital cost accounting data, and national death records. Patients were stratified by heart rate (

Background: In February 2014, coverage for cardiac rehabilitation (CR) was expanded by Centers for Medicare & Medicaid to include patients with chronic symptomatic heart failure (HF) on optimal medical therapy with ejection fraction Methods: We analyzed the Get With The Guidelines-HF registry linked to Medicare claims data from 2008-2012 to assess three groups of patients age 65 or older: previously eligible (due to prior MI, CABG, stable angina, heart valve surgery, or PCI in the previous 12 months), newly eligible, and ineligible for CR. Ineligible patients met neither criteria. Incidence rate was calculated with Kaplan-Meier estimates and Cox proportional hazard models were used to determine the association of events. Results: Among 51,665 HF patients discharged alive, 27.2% (n=14,053) were newly eligible and 14.5% were previously eligible for CR (n=7477). Newly eligible patients were more likely to be black, have atrial fibrillation and EF < 35%, while having fewer previous hospitalizations than patients previously eligible for CR. Newly eligible and ineligible patients had similar risk for 1-year mortality compared with those previously eligible (adjusted Hazard Ratio [HR] 0.95, 95% Confidence Interval [CI] 0.88-1.02, p-value=0.13 and [HR] 1.05, 95% [CI] 0.98-1.13, p-value=0.17, respectively). However, newly eligible and ineligible patients had lower risk for 1-year readmission compared with those previously eligible (adjusted [HR] 0.89, 95% [CI] 0.85-0.93, p-value Conclusions: The extension of coverage for cardiac rehabilitation has tripled the potentially eligible HF population. As these newly eligible patients are at high risk for adverse outcomes, cardiac rehabilitation should be considered.

Introduction: Despite the use of different definitions for worsening heart failure (WHF) in prior clinical trials and registries, an in-hospital WHF event has consistently been associated with worse patient outcomes. WHF is being considered as a potential endpoint to support drug approval. We combined patients from two acute HF trials conducted by the HF Network (ROSE-AHF and DOSE-AHF) to understand how different WHF definitions are associated with event rates. Methods: WHF was defined as persistent or worsening HF requiring rescue therapy including IV vasoactive agents, ultrafiltration, or mechanical support over 72 hours after randomization in ROSE and also included additional open label loop or thiazide diuretic in DOSE. We assessed the relationship between WHF and the composite endpoint (CE) of re-hospitalization, emergency room visits for HF and mortality through 60 days. We also assessed for a differential relationship of WHF from 0-24 hours, 24-48 hours and 48-72 hours post-randomization. Results: The overall incidence of WHF was 14.6% (24.1% in DOSE and 6.3% in ROSE). Patients who developed WHF had lower baseline systolic blood pressure, less peripheral edema and higher BUN. In the combined dataset, WHF was associated with an increase in the CE (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.11-2.42; p-value 0.01). However, the association between WHF and 60-day outcomes was significant in ROSE but not in DOSE (Table). The development of WHF between 48-72 hours compared with 0-24 hours or 24-48 hours was associated with improved outcomes ([HR] 0.48, 95% CI 0.27 - 0.88, p-value 0.02 and [HR] 0.45, 95% CI 0.26 - 0.78, p-value 0.004, respectively). Conclusions: A WHF definition that incorporated intensification of diuretics increased the event rate but was not associated with worse 60-day outcomes. The timing of a WHF event also had a differential association with outcomes. These data support the use of a standardized WHF definition in clinical trials.

Acute myocardial infarction is a common complication of thrombotic thrombocytopenic purpura (TTP), but rarely the presenting manifestation. Anti-thrombotic therapy for myocardial infarction is rarely utilized in the setting of TTP because of elevated bleeding risk. We report a case of TTP presenting with ST-segment elevation myocardial infarction and treated with thrombolytic therapy. The resultant cardiac and neurological complications highlight the challenges of using evidence-based therapy for myocardial infarction in the setting of TTP.

International audience; BACKGROUND:Despite initial in-hospital treatment of acute heart failure (HF), some patients experience worsening HF (WHF). There are limited data about the outcomes and characteristics of patients who experience in-hospital WHF.METHODS AND RESULTS:We assessed the characteristics and outcomes of patients with and without WHF in the ASCEND-HF trial. Worsening HF was defined as at least 1 symptom or sign of new, persistent, or WHF requiring additional intravenous inotropic/vasodilator or mechanical therapy during index hospitalization. We assessed the relationship between WHF and 30-day mortality, 30-day mortality or HF hospitalization, and 180-day mortality. We also assessed whether there was a differential association between early (days 1-3) vs late (day ≥4) WHF and outcomes. Of 7,141 patients with acute HF, 354 (5%) experienced WHF. Patients with WHF were more often male and had a history of atrial fibrillation or diabetes, lower blood pressure, and higher creatinine. After risk adjustment, WHF was associated with increased 30-day mortality (odds ratio 13.37, 95% CI 9.85-18.14), 30-day mortality or HF rehospitalization (odds ratio 6.78, 95% CI 5.25-8.76), and 180-day mortality (hazard ratio 3.90, 95% CI 3.14-4.86) (all P values < .0001). There was no evidence of a difference in outcomes between early and late WHF (all P values for comparison ≥ .2).CONCLUSIONS:Worsening HF during index hospitalization was associated with worse 30- and 180-day outcomes. Worsening HF may represent an important patient-centered outcome in acute HF and a focus of future treatments.

Smartphone applications (apps) are a novel technique to directly reach people for research and health promotion. The 6th Vital Sign is an iPhone app designed using Apple’s Researchkit to enroll and consent adults in a study that measures a 2-minute walk test using the phone’s accelerometer, self-reported health, and demographics. On April 11, 2016 the app was uploaded into the iTunes store and was viewed in iTunes by 1,111 people during the first 50 days. There were 771 downloads, with 398 adults consenting to participate; 90.7% completed the walk test and 63.1% completed the health assessment. Median age of participants was 54 years, 25% were over 65 years, 58% were female, 89.2% White, and 76.1% were living with a chronic health condition. Participants spanned 27 states. This early phase of the 6th Vital Sign study demonstrates the feasibility of designing and disseminating a smartphone-based app to assess population health.

Source Citation Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92. 24716680

Heart failure patients are classified by ejection fraction (EF) into distinct groups: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). Although patients with heart failure commonly have multiple comorbidities that complicate management and may adversely affect outcomes, their role in the HFpEF and HFrEF groups is not well-characterized. This review summarizes the role of noncardiac comorbidities in patients with HFpEF versus HFrEF, emphasizing prevalence, underlying pathophysiologic mechanisms, and outcomes. Pulmonary disease, diabetes mellitus, anemia, and obesity tend to be more prevalent in HFpEF patients, but renal disease and sleep-disordered breathing burdens are similar. These comorbidities similarly increase morbidity and mortality risk in HFpEF and HFrEF patients. Common pathophysiologic mechanisms include systemic and endomyocardial inflammation with fibrosis. We also discuss implications for clinical care and future HF clinical trial design. The basis for this review was discussions between scientists, clinical trialists, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum. (C) 2014 by the American College of Cardiology Foundation.

Cardiac fatigue and elevations in cardiac biomarkers have been described following prolonged exertion in endurance athletes. We comprehensively evaluated a highly trained 46-year-old man attempting a North American transcontinental run in a record time of 45 consecutive days. After running 1460 km and ascending over 2600 m, the run was ended prematurely on day 17 following a leg injury; in support of the event, the subject cycled an additional 1580 km. Echocardiography and biomarker analysis performed pre-event and while running revealed no decrement in systolic function and undetectable levels of troponin I and T. Post-event cardiac MRI demonstrated the interval appearance of delayed enhancement of gadolinium at the inferior insertion of the right ventricle and in the interventricular septum—a novel finding that may represent subtle inflammation secondary to a combined exercise and altitude effect.

Source Citation Kotecha D, Holmes J, Krum H, et al; Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual...

was the primary indication for device placement (n59), followed by chronic ischemic cardiomyopathy (n53) and cardiac transplant rejection (n51). The average duration of Impella support was 1167.5 days. Within 24 hours of device placement, patients had an increase in cardiac output to 5.5L/min61.4 vs 4.4L/min61.3 (p50.005), which was associated with an improvement in GFR from 45.0613.5 to 52.0614.5 (p50.01), pulmonary artery pressures 41 613.0 to 3167.0 (p50.01), right atrial pressures 11 64 to 1066 (p50.04) and pulmonary capillary wedge pressure 326 12.0 to 2065.0 (p50.03). In 84% of cases (n511), the Impella provided adequate left ventricular support, with patients either successfully weaned off support completely (n54), or receiving permanent LVADs (n55) or cardiac transplant (n52). Only 16% of patients (n52) died while actively on the Impella .The 30 day mortality was 23% (n53), while overall mortality at 90 days stood at 54% (n57). The causes of mortality included device malfunction, fatal arrhythmia 24 hours after Impella removal and withdrawal of care in 1 patient each and multi-organ failure in 4 patients who were transitioned to permanent LVAD’s. Conclusions: The Impella 5.0 has been shown to be a safe and efficacious device for use in patients with cardiogenic shock. In our high risk population, the device was easily and quickly inserted and demonstrated consistent hemodynamic augmentation. It also established itself as a good supportive modality in our acutely ill patients as well. Though our overall results in terms of mortality have not been very encouraging, the Impella was indeed successful in bridging patients to either, a permanent LVAD, transplant or in some cases ventricular recovery as well. Therefore in these high risk patients with profound cardiogenic shock, this is indeed a suitable treatment strategy.

Recent data suggest that statins may attenuate exercise training (ET) response, but limited data exist in patients with heart failure (HF), many of whom use statins. HF-ACTION was a randomized, controlled (usual care vs ET) trial of 2,331 chronic ambulatory HF patients with ejection fraction ≤ 35