Optimal Medical Therapy and Outcomes Among Patients With Chronic Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Optimal medical therapy (OMT) scoring may stratify clinical risk in real-world chronic heart failure with reduced ejection fraction (HFrEF) by integrating use and dosing of guideline-directed medical therapy (GDMT) for HFrEF. OBJECTIVES: The purpose of this study was to characterize patients and associated long-term clinical outcomes by OMT score-derived treatment groups. METHODS: CHAMP-HF (Change the Management of Patients with Heart Failure) included U.S. outpatients with chronic HFrEF receiving ≥1 GDMT. OMT subgroups were defined as suboptimal (score <3), acceptable (score = 3), and optimal (score ≥4) by baseline use and dose of GDMT, as proposed by the HF Collaboratory consortium. Cox proportional hazard analyses were used to assess for all-cause and cardiovascular death across subgroups, after adjusting for demographic and clinical covariates. RESULTS: The authors studied 4,582 participants enrolled in CHAMP-HF with available 2-year follow-up. Median age was 68 years, 1,327 (29%) were women, and 2,842 (62%) were White, non-Hispanic. Median OMT score across the population was 4 (Q1-Q3: 2-5), and 1,628 (35%) had suboptimal, 665 (14%) had acceptable, and 2,289 (50%) had optimal therapy. Participants with optimal treatment were younger, had higher annual household income, and were enrolled from practices with dedicated HF clinics (all P < 0.001) than participants with acceptable or suboptimal treatment. Participants with optimal treatment had lower all-cause death (adjusted HR: 0.77; 95% CI: 0.64-0.92) and cardiovascular death (adjusted HR: 0.79; 95% CI: 0.65-0.96) than those with suboptimal treatment. CONCLUSIONS: Across a large cohort of chronic ambulatory HFrEF, OMT scores stratified risk of all-cause and cardiovascular death.

Antibody gene features associated with binding and functional activity in malaria vaccine-derived human mAbs.

The impact of adjuvants on malaria vaccine-induced antibody repertoire is poorly understood. Here, we characterize the impact of two adjuvants, Alhydrogel® and AS01, on antibody clonotype diversity, binding and function, post malaria vaccination. We expressed 132 recombinant anti-Pfs230D1 human monoclonal antibodies (mAbs) from participants immunized with malaria transmission-blocking vaccine Pfs230D1, formulated with either Alhydrogel® or AS01. Anti-Pfs230D1 mAbs generated by Alhydrogel® formulation showed higher binding frequency to Pfs230D1 compared to AS01 formulation, although the frequency of functional mAbs was similar between adjuvant groups. Overall, the AS01 formulation induced anti-Pfs230D1 functional antibodies from a broader array of germline sequences versus the Alhydrogel® formulation. All mAbs using IGHV1-69 gene from the Alhydrogel® cohort bound to recombinant Pfs230D1, but did not block parasite transmission to mosquitoes, similar to the IGHV1-69 mAbs isolated from the AS01 cohort. These findings may help inform vaccine design and adjuvant selection for immunization with Plasmodium antigens.

Feasibility of a Novel Augmented 6-Minute Incremental Step Test: A Simplified Cardiorespiratory Fitness Assessment Tool.

Background: The cardiopulmonary exercise test (CPET) is considered a gold standard in assessing cardiorespiratory fitness (CRF) but has limited accessibility due to competency requirements and cost. Incorporating portable sensor devices into a simple bedside test of CRF could improve diagnostic and prognostic value. Objectives: The authors sought to evaluate the association of an augmented 6-minute incremental step test (6MIST) with standard CPET. Methods: We enrolled patients undergoing clinically indicated supine cycle ergometry CPET with invasive hemodynamics (iCPET) for the same-day 6MIST. CRF-related variables were simultaneously recorded using a signal morphology-based impedance cardiograph (PhysioFlow Enduro) and a portable metabolic analyzer (VO2 Master Pro) during incremental pace stationary stepping. The correlation between CPET and hemodynamic parameters from both tests was assessed using the intraclass correlation coefficient (ICC). Results: Fifteen patients (mean age 60 ± 14 years, 40% female, 27% Black) were included. All patients who agreed to undergo 6MIST completed the study without any test-related adverse events. We observed good to excellent correlation between iCPET- and 6MIST-measured CPET parameters: peak heart rate (ICC = 0.60; 95% CI: 0.15-0.85), absolute peak O2 consumption (VO2) (ICC = 0.77; 95% CI: 0.44-0.92), relative peak VO2 (ICC = 0.64; 95% CI: 0.20-0.86), maximum ventilation (ICC = 0.59; 95% CI: 0.13-0.84), O2 pulse (ICC = 0.71; 95% CI: 0.33-0.89), and cardiorespiratory optimal point (ICC = 0.82; 95% CI: 0.52-0.94). No significant correlation was determined between iCPET and 6MIST in measuring cardiac index at rest (ICC = 0.19; 95% CI: -0.34 to 0.63) or at peak exercise (ICC = 0.36; 95% CI: -0.17 to 0.73). Conclusions: We demonstrate the feasibility of a novel augmented 6MIST with wearable devices for simultaneous CPET and hemodynamic assessment. 6MIST-measured CPET parameters were strongly correlated with the iCPET-derived measurements. Additional studies are needed to confirm the validity of the 6MIST compared to standard upright CPET.

Aortic Root Thromboembolism and Associated Acute Myocardial Infarction in Patients With Contemporary Durable LVADs.

Patients with HeartMate 3 left ventricular assist devices may develop aortic root thrombus, yet its prevalence and associated risks are unknown. We present 2 patients who developed aortic root thromboembolism and acute coronary occlusions. We additionally present heart transplantation as viable treatment for thromboembolic disease and refractory right ventricular failure.

Regional variation in cause of death in patients with type 2 diabetes: Insights from EXSCEL.

AIMS: Type 2 diabetes (T2D) is a risk factor for cardiovascular and non-cardiovascular mortality. However, global distribution of cause-specific deaths in T2D is poorly understood. We characterized cause-specific deaths by geographic region among individuals with T2D at risk for cardiovascular disease (CVD). METHODS AND RESULTS: The international EXSCEL trial included 14,752 participants with T2D (73% with established CVD). We identified the proportion of deaths over 5-year follow-up attributed to cardiovascular and non-cardiovascular causes, and associated risk factors. During median 3.2-year follow-up, 1,091 (7.4%) participants died. Adjudicated causes of death were 723 cardiovascular (66.3% of deaths), including 252 unknown, and 368 non-cardiovascular (33.7%). Most deaths occurred in North America (N = 356/9.6% across region) and Eastern Europe (N = 326/8.1%), with fewest in Asia/Pacific (N = 68/4.4%). The highest proportional cause-specific deaths by region were sudden cardiac in Asia/Pacific (23/34% of regional deaths) and North America (86/24%); unknown in Eastern Europe (90/28%) and Western Europe (39/21%); and non-malignant non-cardiovascular in Latin America (48/31%). Cox proportional hazards model for adjudicated causes of death showed prognostic risk factors (hazard ratio [95% CI]) for cardiovascular and non-cardiovascular deaths, respectively: heart failure 2.04 (1.72-2.42) and 1.86 (1.46-2.39); peripheral artery disease 1.83 (1.54-2.18) and 1.78 (1.40-2.26); and current smoking status 1.61 (1.29-2.01) and 1.77 (1.31-2.40). CONCLUSIONS: In a contemporary T2D trial population, with and without established CVD, leading causes of death varied by geographic region. Underlying mechanisms leading to variability in cause of death across geographic regions and its impact on clinical trial endpoints warrant future research.

Improving Guideline-Directed Medical Therapy for Patients With Heart Failure With Reduced Ejection Fraction: A Review of Implementation Strategies.

Despite recent advances in the use of guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF), achievement of target GDMT use and up-titration to goal dosages continue to be modest. In recent years, a number of interventional approaches to improve the usage of GDMT have been published, but many are limited by single-center experiences with small sample sizes. However, strategies including the use of multidisciplinary teams, dedicated GDMT titration algorithms and clinician audits with feedback have shown promise. There remains a critical need for large, rigorous trials to assess the utility of differing interventions to improve the use and titration of GDMT in HFrEF. Here, we review existing literature in GDMT implementation for those with HFrEF and discuss future directions and considerations in the field.

Electronic health record characterization and outcomes of heart failure with preserved ejection fraction.

BACKGROUND: Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population. METHODS: We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H2FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years. RESULTS: There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations. CONCLUSIONS: Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.

Long-term outcomes of phenoclusters in severe tricuspid regurgitation.

AIMS: Severe tricuspid regurgitation (TR) exhibits high 1-year morbidity and mortality, yet long-term cardiovascular risk overall and by subgroups remains unknown. This study characterizes 5-year outcomes and identifies distinct clinical risk profiles of severe TR. METHODS AND RESULTS: Patients were included from a large US tertiary referral center with new severe TR by echocardiography based on four-category American Society of Echocardiography grading scale between 2007 and 2018. Patients were categorized by TR etiology (with lead present, primary, and secondary) and by supervised recursive partitioning (survival trees) for outcomes of death and the composite of death or heart failure hospitalization. The Kaplan-Meier estimates and Cox regression models were used to evaluate any association by (i) TR etiology and (ii) groups identified by survival trees and outcomes over 5 years. Among 2379 consecutive patients with new severe TR, median age was 70 years, 61% were female, and 40% were black. Event rates (95% confidence interval) were 30.9 (29.0-32.8) events/100 patient-years for death and 49.0 (45.9-52.2) events/100 patient-years for the composite endpoint, with no significant difference by TR etiology. After applying supervised survival tree modeling, two separate groups of four phenoclusters with distinct clinical prognoses were separately identified for death and the composite endpoint. Variables discriminating both outcomes were age, albumin, blood urea nitrogen, right ventricular function, and systolic blood pressure (all P < 0.05). CONCLUSION: Patients with newly identified severe TR have high 5-year risk for death and death or heart failure hospitalization. Partitioning patients using supervised survival tree models, but not TR etiology, discriminated clinical risk. These data aid in identifying relevant subgroups in clinical trials of TR and clinical risk/benefit analysis for TR therapies.

Practical Patient Care Considerations With Use of Vericiguat After Worsening Heart Failure Events.

Vericiguat is a soluble guanylate cyclase stimulator approved by multiple global regulatory bodies and recommended in recently updated clinical practice guidelines to reduce morbidity and mortality in patients with worsening chronic heart failure (HF) with reduced ejection fraction (HFrEF). Despite the growing armaments of evidence-based medical therapy for HFrEF that have demonstrated clinical outcome benefits, there is a need to address residual risk following worsening HF events. When considering therapies aimed to mitigate postevent cardiovascular risk, potential barriers preventing the prescription of vericiguat in eligible patients may include providers' lack of familiarity with it, clinical inertia, limited knowledge about monitoring response to therapy, and concerns about potential adverse effects as well as integration of its routine use during an era of in-person and telehealth hybrid ambulatory care. This review provides an overview of vericiguat therapy and proposes an evidence-based and practical guidance strategy toward implementing its use in various clinical settings. This review additionally summarizes patient counseling points for its initiation and maintenance.

Pressure-Volume Profiles in Heart Failure Across Sexes and Phenotypes.

Studies have shown poor correlation between intra-cardiac pressures and blood volume (BV) measurements including HF. The impact of sex and left ventricular ejection fraction (LVEF) on this relationship has not been studied. We obtained pressure (pulmonary artery diastolic pressure (PADP)) and volume (total blood volume (TBV) and estimated stress blood volume (eSBV)) measurements from HF patients at the time of CardioMEMS implantation. A total of 20 patients were included. There was no significant difference between PADP, TBV, and eSBV between sexes. There was only a moderate correlation between PADP and eSBV in men but not in women or with TBV in both sexes. HFrEF had higher PADP and eSBV than HFpEF. There was a consistent lack of correlation between PADP and both TBV and eSBV. Further studies evaluating mid- to long-term implications of pressure-volume profiles as well as changes following decongestion therapy are warranted to better understand the pressure-volume interplay and determine appropriate decongestion strategy for each pressure-volume phenotype.

In-Hospital Virtual Peer-to-Peer Consultation to Increase Guideline-Directed Medical Therapy for Heart Failure: A Pilot Randomized Trial.

BACKGROUND: Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) improves clinical outcomes and quality of life. Optimizing GDMT in the hospital is associated with greater long-term use in HFrEF. This study aimed to describe the efficacy of a multidisciplinary virtual HF intervention on GDMT optimization among patients with HFrEF admitted for any cause. METHODS: In this pilot randomized, controlled study, consecutive patients with HFrEF admitted to noncardiology medicine services for any cause were identified at a large academic tertiary care hospital between May to September 2021. Major exclusions were end-stage renal disease, hemodynamic instability, concurrent COVID-19 infection, and current enrollment in hospice care. Patients were randomized to a clinician-level virtual peer-to-peer consult intervention providing GDMT recommendations and information on medication costs versus usual care. Primary end points included (1) proportion of patients with new GDMT initiation or use and (2) changes to HF optimal medical therapy scores which included target dosing (range, 0-9). RESULTS: Of 242 patients identified, 91 (38%) were eligible and randomized to intervention (N=52) or usual care (N=39). Baseline characteristics were similar between intervention and usual care (mean age 63 versus 67 years, 23% versus 26% female, 46% versus 49% Black, mean ejection fraction 33% versus 31%). GDMT use on admission was also similar. There were greater proportions of patients with GDMT initiation or continuation with the intervention compared with usual care. After adjusting for optimal medical therapy score on admission, changes to optimal medical therapy score at discharge were higher for the intervention group compared with usual care (+0.44 versus -0.31, absolute difference +0.75, adjusted estimate 0.86±0.42; P=0.041). CONCLUSIONS: Among eligible patients with HFrEF hospitalized for any cause on noncardiology services, a multidisciplinary pilot virtual HF consultation increased new GDMT initiation and dose optimization at discharge.

Neighborhood Socioeconomic Disadvantage and Hospitalized Heart Failure Outcomes in the American Heart Association Get With The Guidelines-Heart Failure Registry.

BACKGROUND: Neighborhood socioeconomic status (SES) is associated with worse health outcomes, yet its relationship with in-hospital heart failure (HF) outcomes and quality metrics are underexplored. We examined the association between socioeconomic neighborhood disadvantage and in-hospital HF outcomes for patients from diverse neighborhoods in the Get With The Guidelines-Heart Failure registry. METHODS: SES-disadvantage scores were derived from geocoded US census data using a validated algorithm, which incorporated household income, home value, rent, education, and employment. We examined the association between SES-disadvantage quintiles with all-cause in-hospital mortality, adjusting for demographics and comorbidities. RESULTS: Of 593 053 patients hospitalized for HF between 2017 and 2020, 321 314 (54%) had residential ZIP Codes recorded. Patients from the most compared with least disadvantaged neighborhoods were younger (mean age 67 versus 76 years), more often Black (42% versus 9%) or Hispanic (14% versus 5%), and had higher comorbidity burden. Demographic-adjusted length of stay increased by ≈1.5 hours with each increment in worsening SES-disadvantage quintiles. Adjusted-mortality odds ratios increased with worsening SES-disadvantage quintiles (Ptrend=0.003), and was 28% higher (adjusted OR=1.28 [1.12-1.48]) for the most compared with least disadvantaged neighborhood groups. CONCLUSIONS: Patients hospitalized for HF from disadvantaged neighborhoods were younger and more often Black or Hispanic. SES disadvantage was independently associated with higher in-hospital mortality. Further research is needed to characterize care delivery patterns in disadvantaged neighborhoods and to address social determinants of health among patients hospitalized for HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02693509.

Machine learning to define phenotypes and outcomes of patients hospitalized for heart failure with preserved ejection fraction: Findings from ASCEND-HF.

BACKGROUND: Heart Failure with Preserved Ejection Fraction (HFpEF) is a heterogenous disease with few therapies proven to provide clinical benefit. Machine learning can characterize distinct phenotypes and compare outcomes among patients with HFpEF who are hospitalized for acute HF. METHODS: We applied hierarchical clustering using demographics, comorbidities, and clinical data on admission to identify distinct clusters in hospitalized HFpEF (ejection fraction >40%) in the ASCEND-HF trial. We separately applied a previously developed latent class analysis (LCA) clustering method and compared in-hospital and long-term outcomes across cluster groups. RESULTS: Of 7141 patients enrolled in the ASCEND-HF trial, 812 (11.4%) were hospitalized for HFpEF and met the criteria for complete case analysis. Hierarchical Cluster 1 included older women with atrial fibrillation (AF). Cluster 2 had elevated resting blood pressure. Cluster 3 had young men with obesity and diabetes. Cluster 4 had low resting blood pressure. Mortality at 180 days was lowest among Cluster 3 (KM event-rate 6.2 [95% CI: 3.5, 10.9]) and highest among Cluster 4 (18.8 [14.6, 24.0], P < .001). Twenty four-hour urine output was higher in Cluster 3 (2700 mL [1800, 3975]) than Cluster 4 (2100 mL [1400, 3055], P < .001). LCA also identified four clusters: A) older White or Asian women, B) younger men with few comorbidities, C) older individuals with AF and renal impairment, and D) patients with obesity and diabetes. Mortality at 180 days was lowest among LCA Cluster B (KM event-rate 5.5 [2.0, 10.3]) and highest among LCA Cluster C (26.3 [19.2, 35.4], P < .001). CONCLUSIONS: In patients hospitalized for HFpEF, cluster analysis demonstrated distinct phenotypes with differing clinical profiles and outcomes.