Clinical and Socioeconomic Determinants of Angiotensin Receptor-Neprilysin Inhibitor Prescription at Hospital Discharge in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Angiotensin receptor-neprilysin inhibitor (ARNI) prescription in the United States remains suboptimal despite strong evidence for efficacy and value in heart failure with reduced ejection fraction. Factors responsible for under prescription are not completely understood. Economic limitations may play a disproportionate role in reduced access for some patients. METHODS: This is an analysis of the Get With The Guidelines-Heart Failure registry, supplemented with data from the Distressed Community Index. Data were fit to a mixed-effects regression model to investigate clinical and socioeconomic factors associated with ARNI prescription at hospital discharge. Missing data were handled by multilevel multiple imputation. RESULTS: Of the 136 144 patients included in analysis, 12.6% were prescribed an ARNI at discharge. The dominant determinants of ARNI prescription were ARNI use while inpatient (odds ratio [OR], 72 [95% CI, 58-89]; P<0.001) and taking an ARNI before hospitalization (OR 9 [95% CI, 7-13]; P<0.001). Having an ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB)/ARNI contraindication was associated with lower likelihood of ARNI prescription at discharge (OR, 0.11 [95% CI, 0.10-0.12]; P<0.001). Socioeconomic factors associated with lower likelihood of ARNI prescription included having no insurance (OR, 0.60 [95% CI, 0.50-0.72]; P<0.001) and living in a ZIP Code identified as distressed (OR, 0.81 [95% CI, 0.70-0.93]; P=0.010). The rate of ARNI prescription is increasing with time (OR, 2 [95% CI, 1.8-2.3]; P<0.001 for patients discharged in 2020 as opposed to 2017), but the disparity in prescription rates between distressed and prosperous communities appears to be increasing. CONCLUSIONS: Multiple medical and socioeconomic factors contribute to low rates of ARNI prescription at hospital discharge. Potential targets for improving ARNI prescription rates include initiating ARNIs during hospitalization and aggressively addressing patients' access barriers with the support of inpatient social services and pharmacists.

Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection.

BACKGROUND: Heart transplantation provides a significant improvement in survival and quality of life for patients with end-stage heart disease, however many recipients experience different levels of graft rejection that can be associated with significant morbidities and mortality. Current clinical standard-of-care for the evaluation of heart transplant acute rejection (AR) consists of routine endomyocardial biopsy (EMB) followed by visual assessment by histopathology for immune infiltration and cardiomyocyte damage. We assessed whether the sensitivity and/or specificity of this process could be improved upon by adding RNA sequencing (RNA-seq) of EMBs coupled with histopathological interpretation. METHODS: Up to 6 standard-of-care, or for-cause EMBs, were collected from 26 heart transplant recipients from the prospective observational Clinical Trials of Transplantation (CTOT)-03 study, during the first 12-months post-transplant and subjected to RNA-seq (n = 125 EMBs total). Differential expression and random-forest-based machine learning were applied to develop signatures for classification and prognostication. RESULTS: Leveraging the unique longitudinal nature of this study, we show that transcriptional hallmarks for significant rejection events occur months before the actual event and are not visible using traditional histopathology. Using this information, we identified a prognostic signature for 0R/1R biopsies that with 90% accuracy can predict whether the next biopsy will be 2R/3R. CONCLUSIONS: RNA-seq-based molecular characterization of EMBs shows significant promise for the early detection of cardiac allograft rejection.

Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction. METHODS: Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events. RESULTS: The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; P=0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; P=0.005), whereas the primary outcome was no longer statistically significant. CONCLUSIONS: Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.

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.

Does Race Influence Decision Making for Advanced Heart Failure Therapies?

Background Race influences medical decision making, but its impact on advanced heart failure therapy allocation is unknown. We sought to determine whether patient race influences allocation of advanced heart failure therapies. Methods and Results Members of a national heart failure organization were randomized to clinical vignettes that varied by patient race (black or white man) and were blinded to study objectives. Participants (N=422) completed Likert scale surveys rating factors for advanced therapy allocation and think-aloud interviews (n=44). Survey results were analyzed by least absolute shrinkage and selection operator and multivariable regression to identify factors influencing advanced therapy allocation, including interactions with vignette race and participant demographics. Interviews were analyzed using grounded theory. Surveys revealed no differences in overall racial ratings for advanced therapies. Least absolute shrinkage and selection operator regression selected no interactions between vignette race and clinical factors as important in allocation. However, interactions between participants aged ≥40 years and black vignette negatively influenced heart transplant allocation modestly (-0.58; 95% CI, -1.15 to -0.0002), with adherence and social history the most influential factors. Interviews revealed sequential decision making: forming overall impression, identifying urgency, evaluating prior care appropriateness, anticipating challenges, and evaluating trust while making recommendations. Race influenced each step: avoiding discussing race, believing photographs may contribute to racial bias, believing the black man was sicker compared with the white man, developing greater concern for trust and adherence with the black man, and ultimately offering the white man transplantation and the black man ventricular assist device implantation. Conclusions Black race modestly influenced decision making for heart transplant, particularly during conversations. Because advanced therapy selection meetings are conversations rather than surveys, allocation may be vulnerable to racial bias.

Influence of Age on Efficacy and Safety of Spironolactone in Heart Failure.

OBJECTIVES: The authors examined efficacy and safety of spironolactone by age in the Americas region (N = 1,767) of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. BACKGROUND: Heart failure with preserved ejection fraction disproportionately affects older adults who may exhibit changes in physiology and variable pharmacokinetics. METHODS: TOPCAT enrolled patients with heart failure and a left ventricular ejection fraction ≥45% who were age 50 or older with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 and prior heart failure hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo with a mean follow-up duration of 3.3 years. We assessed treatment effect and safety by protocol-defined age categories (<65, 65 to 74, and ≥75 years). RESULTS: The mean age was 72 ± 10 years (range 50 to 97 years) with 41% over the age of 75 years. Participants ≥75 years were more commonly women and white and had a lower body mass index and estimated glomerular filtration rate compared with the younger age categories. Spironolactone reduced the primary composite outcome compared with placebo across all age categories (p interaction = 0.42). However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; p < 0.001), particularly in older age groups (p interaction = 0.02). Findings in the whole TOPCAT cohort were consistent with results from the Americas region. CONCLUSIONS: In this post hoc, exploratory analysis of the TOPCAT trial data from the Americas region, although there was no effect of age on efficacy, there were considerable effects of age on increased rates of adverse safety outcomes. These results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302).

Sex Differences in Outcomes and Responses to Spironolactone in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of TOPCAT Trial.

OBJECTIVES: This study sought to investigate sex differences in outcomes and responses to spironolactone in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: HFpEF affects women more frequently than men. Sex differences in responses to effects of mineralocorticoid antagonists have not been reported. METHODS: This was an exploratory, post hoc, non-pre-specified analysis of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. Subjects with symptomatic HF and a left ventricular ejection fraction ≥45% were randomized to spironolactone or placebo therapy. Subjects enrolled from the Americas were analyzed. The primary outcome was a composite of cardiovascular (CV) death, cardiac arrest, or HF hospitalization. Secondary outcomes included all-cause mortality, CV, and non-CV mortality and CV, HF, and non-CV hospitalization. Sex differences in outcomes and treatment effects were determined using time-to-event analysis. RESULTS: In total, 882 of 1,767 subjects (49.9%) were women. Women were older with fewer comorbidities but worse patient-reported outcomes. There were no sex differences in outcomes in the placebo arm or in response to spironolactone for the primary outcome or its components. Spironolactone therapy was associated with reduced all-cause mortality in women (hazard ratio: 0.66; p = 0.01) but not in men (pinteraction = 0.02). CONCLUSIONS: In TOPCAT, women and men presented with different clinical profiles and similar clinical outcomes. The interaction between spironolactone and sex in TOPCAT overall and in the present analysis was nonsignificant for the primary outcome, but there was a reduction in all-cause mortality associated with spironolactone therapy in women, with a significant interaction between sex and treatment arm. Prospective evaluation is needed to determine whether spironolactone therapy may be effective for treatment of HFpEF in women. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure-volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber. Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance. Using phospho-site-specific antibodies, we assay the phosphorylation of titin's PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin's stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness.

Effect of Heart Failure With Preserved Ejection Fraction on Nitric Oxide Metabolites.

Endothelial function may be deranged in heart failure with preserved ejection fraction (HFpEF). Serum NO-derived metabolites (NOm) might provide a biochemical surrogate of endothelial function in patients with heart failure (HF). We measured serum NOm in 415 participants in the Penn HF Study. Participants with HFpEF (n = 82) and those whose EF had recovered (Recovered-HF, n = 125) were matched 1:1 to heart failure with reduced ejection fraction (HFrEF) participants based on age, gender, race, tobacco use, and eGFR. Serum NOm levels were quantified after chemical reduction coupled with gas-phase chemiluminescence detection. After adjustment for matching covariates and BMI, HFpEF (34.5 µM; interquartile range [IQR] 25.0, 51.5) participants had lower NOm levels than HFrEF (41.0 µM; IQR 28.3, 58.0; ratio of HFpEF:HFrEF 0.82, 95% confidence interval [CI] 0.67 to 0.99; p = 0.04), which further decreased when adjusted for covariates that affect endothelial function (ratio 0.79, 95% CI 0.65 to 0.98; p = 0.03). There were no differences between HFrEF (34.0; IQR 25.3, 49.0) and matched Recovered-HF (36.0 µM; IQR 25.0, 55.0) or HFpEF and Recovered-HF. Age (+21%/10-year increase, p <0.001) and black race (-28%, p = 0.03) associated with NOm in HFpEF, whereas age (+11%/10-year increase, p = 0.03), current tobacco use (+67%, p = 0.01), and eGFR (p = 0.01) associated with NOm in Recovered-HF. In conclusion, HFpEF participants have reduced NOm compared with HFrEF in this matched cohort. This might suggest either compromised endothelial function or poor dietary intake. Black race was associated with lower NOm in HFpEF.

Biomarker predictors of cardiac hospitalization in chronic heart failure: a recurrent event analysis.

BACKGROUND: Identification of heart failure (HF) patients at risk for hospitalization may improve care and reduce costs. We evaluated 9 biomarkers as predictors of cardiac hospitalization in chronic HF. METHODS AND RESULTS: In a multicenter cohort of 1,512 chronic HF outpatients, we assessed the association between 9 biomarkers and cardiac hospitalization with the use of a recurrent events approach. Over a median follow-up of 4 years, 843 participants experienced ≥ 1 hospitalizations (total 2,178 hospitalizations). B-type natriuretic peptide (BNP) and troponin I (TnI) exhibited the strongest associations with risk of hospitalization (hazard ratio [HR] 3.8 [95% confidence interval (CI) 2.9-4.9] and HR 3.3 [95% CI 2.8-3.9]; 3rd vs 1st tertiles). Soluble Fms-like tyrosine kinase receptor 1 (sFlt-1) exhibited the next strongest association (HR 2.8 [95% CI 2.4-3.4]), followed by soluble Toll-like receptor 2 (HR 2.3 [95% CI 2.0-2.8]) and creatinine (HR 1.9 [95% CI 1.6-2.4]). Within ischemic/nonischemic subgroups, BNP and TnI remained most strongly associated. Except for creatinine, HRs for all biomarkers studied were smaller within the ischemic subgroup, suggesting greater importance of cardiorenal interactions in decompensation of ischemic HF. CONCLUSION: Although BNP and TnI exhibited the strongest associations with hospitalization, etiology-dependent associations for the remaining biomarkers suggest etiology-specific mechanisms for HF exacerbation. sFlt-1 exhibited a strong association with cardiac hospitalization, highlighting its potential role as a biomarker of HF morbidity.

Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.

BACKGROUND: We hypothesized that patients with heart failure (HF) who recover left ventricular function (HF-Recovered) have a distinct clinical phenotype, biology, and prognosis compared with patients with HF with reduced ejection fraction (HF-REF) and those with HF with preserved ejection fraction (HF-PEF). METHODS AND RESULTS: The Penn Heart Failure Study (PHFS) is a prospective cohort of 1821 chronic HF patients recruited from tertiary HF clinics. Participants were divided into 3 categories based on echocardiograms: HF-REF if EF was <50%, HF-PEF if EF was consistently ≥50%, and HF-Recovered if EF on enrollment in PHFS was ≥50% but prior EF was <50%. A significant portion of HF-Recovered patients had an abnormal biomarker profile at baseline, including 44% with detectable troponin I, although in comparison, median levels of brain natriuretic factor, soluble fms-like tyrosine kinase receptor-1, troponin I, and creatinine were greater in HF-REF and HF-PEF patients. In unadjusted Cox models over a maximum follow-up of 8.9 years, the hazard ratio for death, transplantation, or ventricular assist device placement in HF-REF patients was 4.1 (95% confidence interval, 2.4-6.8; P<0.001) and in HF-PEF patients was 2.3 (95% confidence interval, 1.2-4.5; P=0.013) compared with HF-Recovered patients. The unadjusted hazard ratio for cardiac hospitalization in HF-REF patients was 2.0 (95% confidence interval, 1.5-2.7; P<0.001) and in HF-PEF patients was 1.3 (95% confidence interval, 0.90-2.0; P=0.15) compared with HF-Recovered patients. Results were similar in adjusted models. CONCLUSIONS: HF-Recovered is associated with a better biomarker profile and event-free survival than HF-REF and HF-PEF. However, these patients still have abnormalities in biomarkers and experience a significant number of HF hospitalizations, suggesting persistent HF risk.

The vascular marker soluble fms-like tyrosine kinase 1 is associated with disease severity and adverse outcomes in chronic heart failure.

OBJECTIVES: We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF). BACKGROUND: Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined. METHODS: We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years. RESULTS: The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes. CONCLUSIONS: Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.