Urinary Proteomics and Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P=3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P=0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P=0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission. CONCLUSIONS: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood. METHODS: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis. RESULTS: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; ßTOPCAT=0.539; P<0.0001; ßPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; ßTOPCAT=0.571; P<0.0001; ßPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations. CONCLUSIONS: Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death. CONCLUSIONS: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Proteomic Correlates of the Urinary Protein/Creatinine Ratio in Heart Failure With Preserved Ejection Fraction.

Proteinuria is common in heart failure with preserved ejection fraction (HFpEF), but its biologic correlates are poorly understood. We assessed the relation between 49 plasma proteins and the urinary protein/creatinine ratio (UPCR) in 365 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. Linear regression and network analysis were used to represent relations between protein biomarkers and UPCR. Higher UPCR was associated with older age, a greater proportion of female gender, smaller prevalence of previous myocardial infarction, and greater prevalence of diabetes, insulin use, smoking, and statin use, in addition to a lower estimated glomerular filtration rate, hematocrit, and diastolic blood pressure. Growth differentiation factor 15 (GDF-15; ß = 0.15, p <0.0001), followed by N-terminal proatrial natriuretic peptide (NT-proANP; ß = 0.774, p <0.0001), adiponectin (ß = 0.0005, p <0.0001), fibroblast growth factor 23 (FGF-23, ß = 0.177; p <0.0001), and soluble tumor necrosis factor receptors I (ß = 0.002, p <0.0001) and II (ß = 0.093, p <0.0001) revealed the strongest associations with UPCR. Network analysis showed that UPCR is linked to various proteins primarily through FGF-23, which, along with GDF-15, indicated node characteristics with strong connectivity, whereas UPCR did not. In a model that included FGF-23 and UPCR, the former was predictive of the risk of death or heart-failure hospital admission (standardized hazard ratio 1.83, 95% confidence interval 1.49 to 2.26, p <0.0001) and/or all-cause death (standardized hazard ratio 1.59, 95% confidence interval 1.22 to 2.07, p = 0.0005), whereas UPCR was not prognostic. Proteinuria in HFpEF exhibits distinct proteomic correlates, primarily through its association with FGF-23, a well-known prognostic marker in HFpEF. However, in contrast to FGF-23, UPCR does not hold independent prognostic value.

Chronotropic Incompetence after Heart Transplantation Is Associated with Increased Mortality and Decreased Functional Capacity.

INTRODUCTION: The contribution of chronotropic incompetence to reduced exercise tolerance after a heart transplant is well known, but its role as a prognostic marker of post-transplant mortality is unclear. The aim of this study is to examine the relationship between post-transplant heart rate response (HRR) and survival. METHODS: We performed a retrospective analysis of all adult heart transplant recipients at the University of Pennsylvania between the years 2000 and 2011 who underwent a cardiopulmonary exercise test (CPET) within a year of transplant. Follow-up time and survival status were observed through October 2019, using data merged from the Penn Transplant Institute. HRR was calculated by subtracting the resting HR from the peak exercise HR. The association between HRR and mortality was analyzed using Cox proportional hazard models and Kaplan-Meier analysis. The optimal cut-off point for HRR was generated by Harrell's C statistic. Patients with submaximal exercise tests were excluded, defined by a respiratory exchange ratio (RER) cut-off of 1.05. RESULTS: Of 277 patients with CPETs performed within a year post-transplant, 67 were excluded for submaximal exercise. In the 210 included patients, the mean follow-up time was 10.9 years (Interquartile range (IQR) 7.8-14). Resting HR and peak HR did not significantly impact mortality after adjusting for covariates. In a multivariable linear regression analysis, each 10-beat increase in heart rate response was associated with a 1.3 mL/kg/min increase in peak VO2 and a 48 s increase in the total exercise time. Each beat/min increase in HRR was associated with a 3% reduction in the hazard of mortality (HR 0.97; 95% CI 0.96-0.99, p = 0.002). Using the optimal cut-off point generated by Harrell's C statistic, survival was significantly higher in patients with an HRR > 35 beats/min compared to those with an HRR < 35 beats/min (log rank p = 0.0012). CONCLUSION: In heart transplant patients, a low HRR is associated with increased all-cause mortality and decreased exercise capacity. Additional studies are needed to validate whether targeting HRR in cardiac rehabilitation may improve outcomes.

Early Cardiopulmonary Fitness after Heart Transplantation as a Determinant of Post-Transplant Survival.

BACKGROUND: Decreased peak oxygen consumption during exercise (peak Vo2) is a well-established prognostic marker for mortality in ambulatory heart failure. After heart transplantation, the utility of peak Vo2 as a marker of post-transplant survival is not well established. METHODS AND RESULTS: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo2 (%Vo2). A total of 235 patients met inclusion criteria. The median post-transplant %Vo2 was 49% (IQR 42 to 60). Each standard deviation (±14%) increase in %Vo2 was associated with a 32% decrease in mortality in adjusted models (HR 0.68, 95% CI 0.53 to 0.87, p = 0.002). A %Vo2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively. CONCLUSIONS: Post-transplant peak Vo2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo2 post-transplant is modifiable as a target to improve post-transplant longevity.

Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction.

Background: Skeletal muscle (SkM) phenotypic switching is associated with exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have decreased type-1 oxidative fibers and mitochondrial dysfunction, indicative of impaired oxidative capacity. The SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) mice are commonly used in HFpEF pre-clinical studies and demonstrate cardiac, lung, kidney, and white adipose tissue impairments. However, the SkM (specifically the oxidative-predominant, soleus muscle) has not been described in this preclinical HFpEF model. We sought to characterize the soleus skeletal muscle in the HFpEF SAUNA mice and investigate its translational potential. Methods: HFpEF was induced in mice by uninephrectomy, d-aldosterone or saline (Sham) infusion by osmotic pump implantation, and 1% NaCl drinking water was given for 4 weeks. Mice were euthanized, and the oxidative-predominant soleus muscle was collected. We examined fiber composition, fiber cross-sectional area, capillary density, and fibrosis. Molecular analyses were also performed. To investigate the clinical relevance of this model, the oxidative-predominant, vastus lateralis muscle from patients with HFpEF was biopsied and examined for molecular changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis, and inflammation. Results: Histological analyses demonstrated a reduction in the abundance of oxidative fibers, type-2A fiber atrophy, decreased capillary density, and increased fibrotic area in the soleus muscle of HFpEF mice compared to Sham. Expression of targets of interest such as a reduction in mitochondrial oxidative-phosphorylation genes, increased VEGF-α and an elevated inflammatory response was also seen. The histological and molecular changes in HFpEF mice are consistent and comparable with changes seen in the oxidative-predominant SkM of patients with HFpEF. Conclusion: The HFpEF SAUNA model recapitulates the SkM phenotypic switching seen in HFpEF patients. This model is suitable and relevant to study SkM phenotypic switching in HFpEF.

Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

Novel Risk Model to Predict Emergency Department Associated Mortality for Patients Supported With a Ventricular Assist Device: The Emergency Department-Ventricular Assist Device Risk Score.

Background The past decade has seen tremendous growth in patients with ambulatory ventricular assist devices. We sought to identify patients that present to the emergency department (ED) at the highest risk of death. Methods and Results This retrospective analysis of ED encounters from the Nationwide Emergency Department Sample includes 2010 to 2017. Using a random sampling of patient encounters, 80% were assigned to development and 20% to validation cohorts. A risk model was derived from independent predictors of mortality. Each patient encounter was assigned to 1 of 3 groups based on risk score. A total of 44 042 ED ventricular assist device patient encounters were included. The majority of patients were male (73.6%), <65 years old (60.1%), and 29% presented with bleeding, stroke, or device complication. Independent predictors of mortality during the ED visit or subsequent admission included age ≥65 years (odds ratio [OR], 1.8; 95% CI, 1.3-4.6), primary diagnoses (stroke [OR, 19.4; 95% CI, 13.1-28.8], device complication [OR, 10.1; 95% CI, 6.5-16.7], cardiac [OR, 4.0; 95% CI, 2.7-6.1], infection [OR, 5.8; 95% CI, 3.5-8.9]), and blood transfusion (OR, 2.6; 95% CI, 1.8-4.0), whereas history of hypertension was protective (OR, 0.69; 95% CI, 0.5-0.9). The risk score predicted mortality areas under the curve of 0.78 and 0.71 for development and validation. Encounters in the highest risk score strata had a 16-fold higher mortality compared with the lowest risk group (15.8% versus 1.0%). Conclusions We present a novel risk score and its validation for predicting mortality of patients with ED ventricular assist devices, a high-risk, and growing, population.

Endotrophin, a Collagen VI Formation-Derived Peptide, in Heart Failure.

BACKGROUND: Endotrophin, a collagen type VI-derived peptide, mediates metabolic dysregulation, inflammation, and fibrosis in animal models, but has not been studied in human heart failure (HF). METHODS: We examined the association between circulating endotrophin and outcomes in participants suffering from HF with preserved ejection fraction (HFpEF) enrolled in the TOPCAT trial (n=205). Associations were validated in a participant-level meta-analysis (n=810) that included participants with HFpEF from the PHFS study (United States; n=174), PEOPLE cohort (New Zealand; n=168), a randomized trial of vasodilator therapy (United States; n=45), a cohort from Donostia University Hospital and University of Navarra (Spain; n=171), and the TRAINING-HF trial (Spain; n=47). We also assessed associations in HF with reduced ejection fraction in PHFS (n=1,642). RESULTS: Plasma endotrophin levels at baseline were associated with risk of future death (standardized hazard ratio [HR] = 1.74; 95% confidence interval [CI]=1.36-2.24; P<0.001) and death or HF-related hospital admission (DHFA; standardized HR=2.11; 95% CI= 1.67-2.67; P<0.001) in TOPCAT. Endotrophin improved reclassification and discrimination for these outcomes beyond the MAGGIC risk score and NT-proBNP (N-terminal pro b-type natriuretic peptide). Findings were confirmed in the participant-level meta-analysis. In participants with HF with reduced ejection fraction in PHFS, endotrophin levels were associated with death (standardized HR=1.82; 95% CI=1.66-2.00; P<0.001) and DHFA (standardized HR=1.40; 95% CI=1.31-1.50; P<0.001), but the strength of the latter association was substantially lower than for the MAGGIC risk score (standardized HR=1.93; 95% CI=1.76-2.12) and BNP (standardized HR=1.78; 95% CI=1.66-1.92). CONCLUSIONS: Circulating endotrophin levels are independently associated with future poor outcomes in patients with HF, particularly in HFpEF. (Funded by Bristol Myers Squibb; Instituto de Salud Carlos III [Spain] and European Regional Development Fund; European Commission CRUCIAL project; and the U.S. National Institutes of Health National Heart, Lung, and Blood Institute.).

Mental health disorders and emergency resource use and outcomes in ventricular assist device supported patients.

There are limited data describing the prevalence of mental health disorders (MHDOs) in patients with ventricular assist devices (VADs), or associations between MHDOs and resource use or outcomes. We used the Nationwide Emergency Department Sample administrative database to analyze 44,041 ED encounters for VAD-supported adults from 2010 to 2017, to assess the relationship between MHDOs and outcomes in this population. MHDO diagnoses were present for 23% of encounters, and were associated with higher charges and rates of admission, but lower mortality.

Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism.

AIMS: Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants. METHODS AND RESULTS: Fifty-nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak ), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t1/2, Cr ) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO2,peak , VT, and VO2 efficiency than either control group (all P < 0.05). The t1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF. CONCLUSIONS: Heart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.

Comparing cardiovascular magnetic resonance strain software packages by their abilities to discriminate outcomes in patients with heart failure with preserved ejection fraction.

BACKGROUND: Cardiovascular magnetic resonance (CMR) myocardial strain analysis using feature tracking (FT) is an increasingly popular method to assess cardiac function. However, different software packages produce different strain values from the same images and there is little guidance regarding which software package would be the best to use. We explored a framework under which different software packages could be compared and used based on their abilities to differentiate disease from health and differentiate disease severity based on outcome. METHOD: To illustrate this concept, we compared 4-chamber left ventricular (LV) peak longitudinal strain (GLS) analyzed from retrospective electrocardiogram gated cine imaging performed on 1.5 T CMR scanners using three CMR post-processing software packages in their abilities to discriminate a group of 45 patients with heart failure with preserved ejection fraction (HFpEF) from 26 controls without cardiovascular disease and to discriminate disease severity based on outcomes. The three different post-processing software used were SuiteHeart, cvi42, and DRA-Trufistrain. RESULTS: All three software packages were able to distinguish HFpEF patients from controls. 4-chamber peak GLS by SuiteHeart was shown to be a better discriminator of adverse outcomes in HFpEF patients than 4-chamber GLS derived from cvi42 or DRA-Trufistrain. CONCLUSION: We illustrated a framework to compare feature tracking GLS derived from different post-processing software packages. Publicly available imaging data sets with outcomes would be important to validate the growing number of CMR-FT software packages.

Impact of Chronic Obstructive Pulmonary Disease in Heart Failure With Preserved Ejection Fraction.

COPD often coexists with HFpEF, but its impact on cardiovascular structure and function in HFpEF is incompletely understood. We aimed to compare cardiovascular phenotypes in patients with Chronic Obstructive Pulmonary Disease (COPD), Heart Failure with Preserved Ejection Fraction (HFpEF), or both. We studied 159 subjects with COPD alone (n = 48), HFpEF alone (n = 79) and HFpEF + COPD (n = 32). We used MRI and arterial tonometry to assess cardiac structure and function, thoracic aortic stiffness, and measures of body composition. Relative to participants with COPD only, those with HFpEF with or without COPD exhibited a greater prevalence of female sex and obesity, whereas those with HFpEF + COPD were more often African-American. Compared to the other groups, participants with HFpEF and COPD demonstrated a more concentric LV geometry (LV wall-cavity ratio 1.2, 95%CI: 1.1-1.3; p = 0.003), a greater LV mass (67.4, 95%CI: 60.7-74.2; p = 0.03, and LV extracellular volume (49.4, 95%CI: 40.9-57.9; p = 0.002). Patients with comorbid HFpEF + COPD also exhibited greater thoracic aortic stiffness assessed by pulse-wave velocity (11.3, 95% CI: 8.7-14.0 m/s; p = 0.004) and pulsatile load imposed by the ascending aorta as measured by aortic characteristic impedance (139 dsc; 95%CI=111-166; p = 0.005). Participants with HFpEF, with or without COPD, exhibited greater abdominal and pericardial fat, without difference in thoracic skeletal muscle size. In conclusion, individuals with co-morbid HFpEF and COPD have a greater degree of systemic large artery stiffening, LV remodeling, and LV fibrosis than those with either condition alone.

Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction.

Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization.

An Increasing Burden of Disease: Emergency Department Visits Among Patients With Ventricular Assist Devices From 2010 to 2017.

Background With a growing population of patients supported by ventricular assist devices (VADs) and the improvement in survival of this patient population, understanding the healthcare system burden is critical to improving outcomes. Thus, we sought to examine national estimates of VAD-related emergency department (ED) visits and characterize their demographic, clinical, and outcomes profile. Additionally, we tested the hypotheses that resource use increased and mortality improved over time. Methods and Results This retrospective database analysis uses encounter-level data from the 2010 to 2017 Nationwide Emergency Department Sample. The primary outcome was mortality. From 2010 to 2017, >880 million ED visits were evaluated, with 44 042 VAD-related ED visits identified. The annual mean visits were 5505 (SD 4258), but increased 16-fold from 2010 to 2017 (824 versus 13 155). VAD-related ED visits frequently resulted in admission (72%) and/or death (3.0%). Median inflation-adjusted charges were $25 679 (interquartile range, $7450, $63 119) per encounter. The most common primary diagnoses were cardiac (22%), and almost 30% of encounters were because of bleeding, stroke, or device complications. From 2010 to 2017, admission and mortality decreased from 82% to 71% and 3.4% to 2.4%, respectively (P for trends <0.001, both). Conclusions We present the first study using national-level data to characterize the growing ED resource use and financial burden of patients supported by VAD. During the past decade, admission and mortality rates decreased but remain substantial; in 2017 ≈1 in every 40 VAD ED encounters resulted in death, making it critical that clinical decision-making be optimized for patients with VAD to maximize good outcomes.

A Modified Grading System for Early Right Heart Failure Matches Functional Outcomes and Survival After Left Ventricular Assist Devices.

Early right heart failure (ERHF) remains a common complication after continuous-flow left ventricular assist device (cf-LVAD) and has been associated with increased mortality. The specific criteria used to define ERHF remain somewhat arbitrary. Correlating the degree of ERHF with outcomes after LVAD could inform a more clinically relevant definition. We identified 196 patients who underwent first durable cf-LVAD between 2008 and 2015 at a single center. Postimplant ERHF was graded as absent, mild (requiring inotropic support for 14-20 days), moderate (inotropes for ≥ 21 days), or severe (requiring unplanned RVAD at any time during the index hospitalization). ERHF was associated with clinical outcomes including 1 year survival and New York Heart Association (NYHA) class and 6 minute walk distance (6MWD) at 3 and 6 months. Survival was assessed using the Kaplan-Meier method with log-rank testing and multivariate Cox proportional-hazards modeling. Compared to patients without ERHF, those with mild ERHF had similar 1 year survival (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.26-1.80, p = 0.45), while mortality was substantially increased in patients with moderate (HR 2.65, 95% CI: 1.27-5.54, p = 0.009) and severe ERHF (HR 8.16, 95% CI: 3.97-16.76, p < 0.0001). The severity of ERHF was associated with 6MWD at both 3 months (p = 0.001) and 6 months (p = 0.013). The relationship between ERHF and postimplant survival and functional status persisted in multivariate modeling. A simple, modified grading system for ERHF severity is strongly associated with 1 year survival and functional capacity after cf-LVAD. These results argue against using a binary definition for ERHF and suggest the need to modify definition of ERHF severity.

Clinical and Proteomic Correlates of Plasma ACE2 (Angiotensin-Converting Enzyme 2) in Human Heart Failure.

ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.

Peripheral Determinants of Oxygen Utilization in Heart Failure With Preserved Ejection Fraction: Central Role of Adiposity.

The aim of this study was to determine the arteriovenous oxygen content difference (ΔAVo2) in adult subjects with and without heart failure with preserved ejection fraction (HFpEF) during systemic and forearm exercise. Subjects with HFpEF had reduced ΔAVo2. Forearm diffusional conductance for oxygen, a lumped conductance parameter that incorporates all impediments to the movement of oxygen from red blood cells in skeletal muscle capillaries into the mitochondria within myocytes, was estimated. Forearm diffusional conductance for oxygen was not different among adults with HFpEF, those with hypertension, and healthy control subjects; therefore, diffusional conductance cannot explain the reduced forearm ΔAVo2. Instead, adiposity was strongly associated with ΔAVo2, suggesting an active role for adipose tissue in reducing exercise capacity in patients with HFpEF.

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF. METHODS: In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156). RESULTS: Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score. CONCLUSIONS: Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.