Previous heart failure hospitalization, spironolactone, and outcomes in heart failure with preserved ejection fraction - a secondary analysis of TOPCAT.

BACKGROUND: Hospitalization for heart failure (HHF) is associated with poor postdischarge outcomes but the role of time since most recent HHF and potential treatment interactions are unknown. We aimed to assess history of and time since previous HHF, associations with composite of cardiovascular (CV) death and total HHF, first HHF and interactions with randomization to spironolactone, in heart failure with preserved ejection fraction. METHODS AND RESULTS: We assessed these objectives using uni- and multivariable regressions and spline analyses in TOPCAT-Americas. Among 1,765 patients, 66% had a previous HHF. Over a median of 2.9 years, 1,064 composite events of CV death or total HHFs occurred. Previous HHF was associated with more severe HF, and was independently associated with the composite outcome (HR 1.26, 95%CI 1.05-1.52, P = .014), and all secondary outcomes. A shorter time since most recent HHF appeared to be associated with subsequent first HHF, but not the composite of CV death or total HHF. Spironolactone had a significant interaction with previous HHF (interaction-P .046). Patients without a previous HHF had a larger effect of spironolactone on the composite outcome (HR 0.63, 95%CI 0.46-0.87, P = .005) than patients with a previous HHF (HR 0.91, 95%CI 0.78-1.06, P = .224). CONCLUSION: In TOPCAT-Americas, previous HHF was associated with CV death and first and total HHF. Duration since most recent HHF seemed to be associated with time to first HHF only. Spironolactone was associated with better outcomes in patients without a previous HHF. This interaction is hypothesis-generating and requires validation in future trials.

Acyl ghrelin improves cardiac function in heart failure and increases fractional shortening in cardiomyocytes without calcium mobilization.

BACKGROUND AND AIMS: Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes. METHODS AND RESULTS: In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3. CONCLUSION: In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05277415.

Associations between rheumatoid arthritis, incident heart failure, and left ventricular ejection fraction.

BACKGROUND: Rheumatoid arthritis (RA) is an independent risk factor for heart failure (HF). Yet, the association between RA and left ventricular ejection fraction (LVEF) in incident HF is not well studied, nor are outcomes of HF in RA by LVEF. METHODS: We identified incident HF patients between 2003 and 2018 through the Swedish Heart Failure Registry, enriched with data from national health registers. Using logistic regression, associations between a prior diagnosis of RA and LVEF among HF patients and vs age, sex, and geographical area matched general population controls without HF were assessed. Additionally, associations between HF with vs without a prior diagnosis of RA, by LVEF, and outcomes up to 5 years after HF diagnosis were investigated using Cox regression. LVEF was primarily dichotomized at 40% and secondarily categorized as <40%, 40% to 49%, and ≥50%. Covariates included demographics and cardiovascular comorbidities. RESULTS: Among 20,916 incident HF patients, 331 (1.6%) had RA vs 1,047/103,501 (1.0%) of HF-free controls. The odds ratio (OR) for RA was 1.4 (95% CI: 1.1-1.8) in LVEF<40% vs HF-free controls and 1.6 (95% CI: 1.3-2.0) in LVEF≥40% vs HF-free controls. Among HF patients, RA was more common in HF with LVEF ≥40% (1.9%) vs LVEF<40% (1.3%), corresponding to OR 1.4 (95% CI: 1.1-1.7). No associations between RA and cardiovascular outcomes were observed across LVEF. An association between RA and all-cause mortality was observed only for patients with LVEF<40% (hazard ratio: 1.4; 95% CI: 1.1-1.8). CONCLUSIONS: RA was independently associated with incident HF, particularly HF with LVEF≥40%. RA did not associate with cardiovascular outcomes following HF diagnosis but was associated with increased risk of all-cause mortality in HF with LVEF<40%.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD.

RATIONALE: Hyperglycemia -induced reactive oxygen species are key mediators of cardiac dysfunction. JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated. OBJECTIVE: The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species-driven myocardial dysfunction. METHODS AND RESULTS: JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 2) and NOX4 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-κB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α MHC (α- myosin heavy chain) promoter (α MHC JunDtg) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects. CONCLUSIONS: Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

BACKGROUND: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. METHODS: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure. RESULTS: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. CONCLUSIONS: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

The Differential Impact of the Left Atrial Pressure Components on Pulmonary Arterial Compliance-Resistance Relationship in Heart Failure.

BACKGROUND: An increase in the pulmonary capillary wedge pressure (PAWP) has been shown to impact on the inherent relationship between the pulmonary arterial compliance (PAC) and pulmonary vascular resistance (PVR), thus augmenting the pulsatile relative to the resistive load of the right ventricle. However, the PAWP comprises the integration of both the steady and the pulsatile pressure components. We sought to address the differential impact of the these distinct PAWP components on the PAC-PVR relationship in a cohort of patients with heart failure. METHODS AND RESULTS: The study population consisted of 192 patients with hemodynamic findings diagnostic for heart failure. Off-line analysis was performed using the MATLAB software. The steady and pulsatile PAWP components were calculated as mid-A pressure and mean pressure during the V-wave oscillation, respectively. The PAC and PVR were hyperbolically and inversely associated and the subgroup of patients with PAWP above the median (>18 mm Hg) displayed a significant left and downward shift of the curve fit (P < .001). The shift in the PAC-PVR fit between patients with higher versus low steady PAWP was not significant (P = .43). In contrast, there was a significant downward and leftward shift of the PVR-PAC curve fit for the subgroup with a higher pulsatile PAWP (P < .001). Furthermore, only the pulsatile PAWP was significantly associated with the time-constant of the pulmonary circulation, assessed as the PAC × PVR product (P < .001). CONCLUSIONS: In patients with heart failure, the pulsatile rather than the steady PAWP component stands for the previously documented shift of the PAC-PVR relationship occurring at an elevated PAWP.

Generalizability of HFA-PEFF and H2FPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF.

BACKGROUND: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers. METHODS AND RESULTS: Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P < .001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and H2FPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P < .001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis. CONCLUSIONS: Although the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.

Effect of dipeptidyl peptidase-4 inhibitors on complement activation.

BACKGROUND: Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase-4 (DPP-4) is a cell surface serine protease expressed in a variety of tissues. DPP-4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose-lowering action, for example, renoprotective and anti-inflammatory properties, but the exact mechanisms remain unknown. We hypothesised that DPP-4 inhibitors block adverse complement activation by inhibiting complement-activating serine proteases. MATERIALS AND METHODS: We analysed the effects of 7 different DPP-4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan-binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg (n = 34) or placebo (n = 37) for 12 weeks. RESULTS: All the 7 DPP-4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose-dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow-up in both groups without significant effect of sitagliptin. CONCLUSIONS: We demonstrated an inhibitory effect of DPP-4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP-4 inhibitors remains to be fully elucidated.

Reorganization of heart failure management and improved outcome - the 4D HF Project.

OBJECTIVES: Heart failure (HF) management is suboptimal in Sweden despite available evidence-based guidelines. To improve HF treatment, a comprehensive HF management program (4D project) was implemented in the Stockholm County (>2.1 million inhabitants). Design. A standardized care program centralized at five hospital-based HF clinics was implemented in 2014-2017. We registered from 2012 to 2017: (1) numbers of referrals and visits to HF clinics, (2) numbers of hospital admitted patients per million inhabitants, (3) dispensed HF medications after admission, and (4) covariate-adjusted 1-year all-cause mortality or HF readmission. Results. Yearly visits to the five HF outpatient clinics increased 3.4 times from 3,372 to 11,527. Dispensed HF drug prescriptions increased, in particular, for readmitted patients, compared to 2012 (p<.0001). Total number of hospital admitted HF patients as well as new-onset or readmitted HF patients decreased by 16, 13, and 20%, respectively (p < .0001). The combined 1-year mortality or HF readmission over the period was 48% (n = 17,124/35,880) and improved per year (HR 0.98 [0.97-0.99], p < .001) from 2012. Conclusion. A comprehensive standardized care HF management program including expanded HF clinics was associated with improved evidence-based medication, reduced HF hospitalization, and improvement of the combined outcome of 1-year mortality or HF readmission in Stockholm.

A multinational registry to study the characteristics and outcomes of heart failure patients: The global congestive heart failure (G-CHF) registry.

The goal of the global congestive heart failure (G-CHF) registry is to collect comparative international data on heart failure characteristics, management, and outcomes and to better understand the determinants that impact the clinical course of heart failure. METHODS: G-CHF is a multicenter, prospective cohort study of adult patients with a new or prior clinical diagnosis of heart failure. We have enrolled 23,047 participants from 257 centers in 40 countries from 8 major geographic regions of the world, with recruitment ongoing. Approximately 4,000 participants will also participate in substudies to assess frailty, comorbidity, diet, barriers to care, biomarkers, and planned detailed echocardiographic analyses. Follow-up is planned for a period of 5 years. The primary outcome is cause-specific mortality. Key secondary outcomes include hospitalizations, quality of life, and major cardiovascular and noncardiovascular outcomes. A total of 31.9% of participants were enrolled as inpatients. Thus far, mean age of the cohort at baseline is 63.1 years, and 60.8% are male. Participants most commonly have heart failure with reduced ejection fraction (53.6%) followed by preserved ejection fraction (24.2%) and midrange ejection fraction (20.6%). The most common causes of heart failure are ischemic (37.8%) followed by hypertensive (20.0%), idiopathic (15.1%), and valvular disease (8.8%). CONCLUSION: G-CHF will provide a greater understanding of the characteristics of the global heart failure population, variations in its management, clinical outcomes, and what continues to impact morbidity and mortality in this high-risk population.

Increased iron absorption in patients with chronic heart failure and iron deficiency.

BACKGROUND: Iron deficiency (ID) is common in patients with chronic heart failure (CHF), but the underlying causes are not fully understood. We investigated whether ID is associated with decreased iron absorption in patients with CHF. METHODS AND RESULTS: We performed an oral iron-absorption test in 30 patients and 12 controls. The patients had CHF with reduced (n = 15) or preserved (n = 15) ejection fraction and ID, defined as s-ferritin < 100 µg/L, or s-ferritin 100-299 µg/L and transferrin saturation < 20%. The controls had no HF or ID and were of similar age and gender. Blood samples were taken before and 2 hours after ingestion of 100 mg ferroglycin sulphate. The primary endpoint was the delta plasma iron at 2 hours. The delta plasma iron was higher in the group with HF than in the control group (median increase 83.8 [61.5;128.5] µg/dL in HF vs 47.5 [30.7;61.5] µg/dL in controls, P = 0.001), indicating increased iron absorption. There was no significant difference between the groups with preserved or reduced ejection fraction (P = 0.46). CONCLUSION: We found increased iron absorption in patients with CHF and ID compared to controls without ID and HF, indicating that reduced iron absorption is not a primary cause of the high prevalence of ID in patients with CHF. CLINICAL TRIAL REGISTRATION: EudraCT 2017-000158-21.

Do Patients With Acute Heart Failure and Preserved Ejection Fraction Have Heart Failure at Follow-Up: Implications of the Framingham Criteria.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) may be misdiagnosed. We assessed prevalence and consistency of Framingham criteria signs and symptoms in acute vs subsequent stable HFpEF. METHODS: Three hundred ninety-nine patients with acute HFpEF according to Framingham criteria were re-assessed in stable condition. Four definitions of HFpEF at follow-up: (1) Framingham criteria alone, (2) Framingham criteria and natriuretic peptides (NPs), (3) Framingham criteria, NPs, and European Society of Cardiology HF guidelines echocardiographic criteria, (4) Framingham criteria, NPs, and the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON) trial echocardiographic criteria. RESULTS: At follow-up, HFpEF was still present in 27%, 22%, 21%, and 22%, respectively. Most prevalent in acute HFpEF were dyspnea at exertion (90%), pulmonary rales (71%), persisting at follow-up in 70% and 13%, respectively. Characteristics at acute HF with greater or lesser odds of stable HFpEF; (1) jugular venous distention (odds ratio [OR] 1.80, 95% confidence interval [CI] 1.13-2.87; P = .013) and pleural effusion (OR 0.45, 95% CI 0.24-0.85; P = .014) and (4), older age (1.04, 95% CI 1.01-1.08; P = .014) and tachycardia (>100 bpm) 0.52, 95% CI 0.27-1.00; P = .048). CONCLUSIONS: In patients with acute HFpEF, one-quarter met the HF definition according to Framingham criteria at ambulatory follow-up. The proportion of patients with postdischarge HFpEF was largely unaffected by additional echocardiographic or NP criteria Older age and jugular venous distention at acute presentation predicted persistent HFpEF at follow-up, whereas pleural effusion and tachycardia may yield false HFpEF diagnoses. This finding has implications for HFpEF trial design.

Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction: A Follow-up in the PROMIS-HFpEF Study.

BACKGROUND: Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF. METHODS AND RESULTS: We assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of <2.5. Time to CV death/first hospitalization was compared by log-rank test and recurrent HF and all-cause hospitalizations by Poisson test. Of 263 patients enrolled, 257 were evaluable at 1 year. Where the coronary flow reserve was interpretable (n = 201), CMD was present in 150 (75%). The median follow-up was 388 days (Q1, Q3 365, 418). The outcome of CV death/first HF hospitalization occurred in 15 patients (4 CV deaths). The incidence rate was in CMD 96 per 1000 person-years, 95% confidence interval 54-159, vs non-CMD 0 per1000 person-years, 95% confidence interval 0-68, P = .023, and remained significant after accounting for selected clinical variables. In patients with CMD, the incidence rates were significantly higher also for CV death/recurrent HF hospitalizations, all-cause death/first HF, and recurrent but not first all-cause hospitalization. CONCLUSIONS: In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CV- and HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF.

Metabolomic Profile in HFpEF vs HFrEF Patients.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications. METHODS AND RESULTS: In new-onset HFpEF (EF of ≥50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, l-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (Pinteraction = .020). CONCLUSIONS: Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov.

ST2 in heart failure with preserved and reduced ejection fraction.

OBJECTIVES: Soluble suppression of tumorigenecity 2 (sST2) is prognostic in acute and chronic heart failure with reduced ejection fraction (HFrEF) but less studied in HF with preserved EF (HFpEF). We evaluated sST2 concentrations, correlations with biomarkers and echocardiographic measures of diastolic and systolic function, and associations with outcomes in HFpEF and HFrEF. DESIGN AND RESULTS: A total of 193 subjects from three different cohorts were included. Eighty-six HFpEF patients were obtained from the Karolinska Rennes (KaRen) study, 86 patients with HFrEF were recruited from referrals to Karolinska University Hospital for advanced assessment of HF, and 21 controls were included (ClinicalTrials.gov Identifier for KaRen: NCT01091467). HFrEF and controls cohorts did not have ClinicalTrials.gov registrations. sST2 was lower in HFpEF, median (interquartile range); 23 (17-31) compared to HFrEF; 35 (23-52) µg/L, p < .001. In both HFpEF and HFrEF, sST2 correlated positively with NT-proBNP (HFpEF rs=0.392, p < .001 and HFrEF rs=0.466, p < .001). In HFpEF, sST2 correlated to left atrial volume index (rs=0.276, p = .019) but not to E/E´, nor to left ventricular mass index. sST2 was in HFpEF associated with the composite endpoint of death or HF hospitalization, adjusted hazard ratio (HR) per log increase in sST2 6.62, 95% confidence interval (CI) 1.04-42.28, p = .046, and in HFrEF death, heart transplant or left ventricular assist systems; 3.51, 95% CI 1.05-11.69, p = .041. CONCLUSIONS: In patients with HFpEF compared to HFrEF, crude levels of sST2 were lower but potentially more strongly associated with outcomes. The lower levels of sST2 in HFpEF than in HFrEF may reflect lower degrees of fibrosis, but the potentially stronger association with outcomes may reflect a greater prognostic importance of progressive fibrosis and as such a greater potential for intervention. In conclusion; this study adds to the evidence of sST2 as prognostic marker in both HFpEF and HFrEF.

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF.

Aims: To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. Methods and results: This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). Conclusions: PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

Associations With and Prognostic and Discriminatory Role of N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Versus Mid-range Versus Reduced Ejection Fraction.

BACKGROUND: The aim of this study was to characterize N-terminal pro-B-type natriuretic peptide (NT-proBNP) in terms of determinants of levels and of its prognostic and discriminatory role in heart failure with mid-range (HFmrEF) versus preserved (HFpEF) and reduced (HFrEF) ejection fraction. METHODS AND RESULTS: In 9847 outpatients with HFpEF (n = 1811; 18%), HFmrEF (n = 2122; 22%) and HFrEF (n = 5914; 60%) enrolled in the Swedish Heart Failure Registry, median NT-proBNP levels were 1428, 1540, and 2288 pg/mL, respectively. Many determinants of NT-proBNP differed by ejection fraction, with atrial fibrillation (AF) more important in HFmrEF and HFpEF, diabetes and hypertension in HFmrEF, and age and body mass index in HFrEF and HFmrEF, whereas renal function, New York Heart Association functional class, heart rate, and anemia were similar. Hazard ratios for death and death/HF hospitalization for NT-proBNP above the median ranged from 1.48 to 2.00 and were greatest for HFmrEF and HFpEF. Areas under the receiver operating characteristic curve for death and death/HF hospitalization were greater in HFmrEF than in HFpEF and HFrEF and were reduced by AF in HFpEF and HFmrEF but not in HFrEF. CONCLUSIONS: In HFpEF and especially HFmrEF, NT-proBNP was more prognostic and discriminatory, but also more affected by confounders such as AF. These data support the use of NT-proBNP for eligibility, enrichment, and surrogate end points in HFpEF and HFmrEF trials, and suggest that cutoff levels for eligibility should be carefully tailored to comorbidity.

HFpEF and HFrEF Display Different Phenotypes as Assessed by IGF-1 and IGFBP-1.

BACKGROUND: Anabolic drive is impaired in heart failure with reduced ejection fraction (HFrEF) but insufficiently studied in heart failure with preserved ejection fraction (HFpEF). Insulin-like growth factor 1 (IGF-1) mediates growth hormone effects and IGF binding protein 1 (IGFBP-1) regulates IGF-1 activity. We tested the hypothesis that HFpEF and HFrEF are similar with regard to IGF-1 and IGFBP-1. METHODS AND RESULTS: In patients with HFpEF (n = 79), HFrEF (n = 85), and controls (n = 136), we analyzed serum IGF-1 and IGFBP-1 concentrations, correlations, and associations with outcome. Age-standardized scores of IGF-1 were higher in HFpEF, median arbitrary units (interquartile range); 1.21 (0.57-1.96) vs HFrEF, 0.09 (-1.40-1.62), and controls, 0.22 (-0.47-0.96), P overall <.001. IGFBP-1 was increased in HFpEF, 48 (28-79), and HFrEF, 65 (29-101), vs controls, 27(14-35) µg/L, P overall <.001. These patterns persisted after adjusting for metabolic and HF severity confounders. IGF-1 was associated with outcomes in HFrEF, hazard ratio per natural logarithmic increase in IGF-1 SD score 0.51 (95% confidence interval 0.32-0.82, P = .005), but not significantly in HFpEF. IGFBP-1 was not associated with outcomes in either HFpEF nor HFrEF. CONCLUSION: HFpEF and HFrEF phenotypes were similar with regard to increased IGFBP-1 concentrations but differed regarding IGF-1 levels and prognostic role. HFrEF and HFpEF may display different impairment in anabolic drive.