Treatment Of Preserved Cardiac Function Heart Failure With An Aldosterone Antagonist Research Articles

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

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. 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. 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.

Prognostic Value of Depressive Symptoms for Cardiovascular Events in Female Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.

Among those with heart failure (HF), women are more likely to develop depression than men. Few studies have focused on the outcomes of female patients with HF with depressive symptoms. A total of 506 female patients with HF with preserved ejection fraction were included in this secondary analysis from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) cohort, and 439 female patients with HF with reduced ejection fraction were included from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) cohort. Depressive symptoms were measured using the Patient Health Questionnaire-9 and Beck Depression Inventory-II. The depression class was categorized by severity, and the change in clinical depression class was defined as aggravated (1-grade increase) or improved (1-grade decrease). The prognostic value of depressive symptoms was determined by using multivariable Cox proportional hazards models. Female patients with improved depressive symptoms had worse depressive status at baseline and lower baseline Kansas City Cardiomyopathy Questionnaire scores. Depression class at the 12-month visit and depression class change were the dominant prognostic factors for cardiovascular death in female patients with HF with preserved ejection fraction (hazard ratio [HR], 1.43 [95% CI, 1.02-2.01], P=0.036; HR, 1.71 [95% CI, 1.14-2.55], P=0.009). Among the patients with HF with reduced ejection fraction, both the depression class at baseline and depression class change had significant prognostic effects on cardiovascular death (HR, 3.30 [95% CI, 1.70-6.39], P<0.001; HR, 2.21 [95% CI, 1.28-3.80], P=0.004). However, the prognostic value of depressive assessments for hospitalization in patients with HF is unclear. In female patients with HF with reduced ejection fraction, the depression class at baseline was most strongly associated with cardiovascular death, whereas in female patients with HF with preserved ejection fraction, the change in depression class exhibited a more significant prognostic trend.

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

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. 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. 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; βTOPCAT=0.539; P<0.0001; βPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; βTOPCAT=0.571; P<0.0001; βPHFS=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. 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.

Echocardiographic characterization of patients with supranormal ejection fraction: pooled core laboratory analysis of the TOPCAT and PARAGON-HF trials

Abstract Background Patients with heart failure and supranormal ejection fraction (HFsnEF) may be phenotypically distinct from those with normal or below normal left ventricular ejection fraction (LVEF), and may demonstrate different prognostic trajectories or treatment responses. Purpose To characterize clinical features, cardiac structure and function among patients with HF with preserved EF (defined as 45% ≤ LVEF ≤ 65%) and supranormal EF (defined as LVEF&amp;gt;65%). Methods Baseline clinical characteristics and key echocardiographic parameters from patients enrolled in the echocardiographic substudies of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)-Americas and PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blocker] Global Outcomes in Heart Failure with Preserved Ejection Fraction) were compared between patients with and without HFsnEF. Results Among 1,751 participants (mean age 73 years old, 51% women) in this pooled core laboratory analysis, 265 (15%) had HFsnEF. Participants in HFsnEF group were more likely to be women, and less likely to have prior myocardial infarction and atrial fibrillation (Table 1). Compared with those with LVEF ≤ 65%, those with LVEF &amp;gt; 65% had lower LV end-diastolic and end-systolic volume indices, lower LV mass index, higher LV relative wall thickness, and higher right ventricular fractional area change. LV geometry and measures of LV diastolic function were similar in both groups (Table 1). Global longitudinal strain (GLS) was abnormal (absolute GLS &amp;lt;16%) in 28% in those with HFsnEF compared with 53% in those with LVEF ≤ 65%. After adjusting for baseline LV ejection fraction and sex, and stratified by trial, abnormal GLS was associated with a higher risk of composite of first heart failure hospitalization or cardiovascular death (overall hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.23 – 1.98, P &amp;lt; 0.001), cardiovascular death (overall HR 2.06, 95% CI 1.35 – 3.13, P = 0.001), and heart failure hospitalization (overall HR 1.49, 95% CI 1.15 – 1.93, P = 0.003) in both HFsnEF and non-HFsnEF groups (P-interaction &amp;gt; 0.05 for all, Figure 1). Conclusions Among participants in the TOPCAT-Americas and PARAGON-HF trials, those with LVEF &amp;gt; 65% were predominantly women, had less LV remodeling, and had better RV function based on echocardiographic measures. Nevertheless, despite supranormal LVEF, GLS was abnormal in over a quarter of patients and remained an important predictor of adverse clinical outcomes in this cohort.Table 1Figure 1

Comparative Outcomes of a Transthyretin Amyloid Cardiomyopathy Cohort Versus Patients With Heart Failure With Preserved Ejection Fraction Enrolled in the TOPCAT Trial.

Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; P=0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; P=0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; P<0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; P=0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; P=0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; P<0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.

Body mass index and clinical outcomes in patients with heart failure with preserved ejection fraction mediated by diastolic blood pressure status?

BackgroundThe “obesity paradox” has been elucidated in patients with heart failure (HF). Current guidelines introduce a target diastolic blood pressure (DBP) < 80 mmHg but >70 mmHg in HF patients. Due to reduced coronary perfusion, low DBP has a deleterious impact on cardiovascular outcomes. This present study aimed to assess the relationship between BMI and adjudicated clinical outcomes in HFpEF patients according to the status of DBP. MethodsWe analyzed the data in 1749 HFpEF patients from the Americas of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) Trial. The population was stratified by DBP (<70 mmHg, and ≥70 mmHg) and BMI strata (normal weight, overweight, and obesity). Cox proportional hazards models and competing-risks regression analysis were performed. ResultsAt baseline, the median BMI and DBP were 32.9 kg/m2 (interquartile range 28.0–38.5 kg/m2) and 70 mmHg (interquartile range 62–80 mmHg), respectively. In the multivariable analysis, obesity was associated with better survival rates in the total HFpEF population (all-cause death: HR = 0.439, 95% CI 0.256–0.750; and cardiovascular death: HR = 0.378, 95% CI 0.182–0.787). In patients with DBP<70 mmHg, obesity was not significantly associated with reduced risks for all-cause death (HR = 0.531, 95% CI: 0.263–1.704) and cardiovascular death (HR = 0.680, 95% CI: 0.254–1.819). However, multivariate analyses for cardiovascular death (HR = 0.339, 95% CI: 0.117–0.983) and all-cause death (HR = 0.389, 95% CI: 0.156–0.969) were significant in patients with DBP≥70 mmHg. Nevertheless, there were no interactions between DBP and BMI. ConclusionsThe obesity paradox was observed in patients with HFpEF, regardless of DBP strata (<70 mmHg, and ≥70 mmHg).

Steroidal MRA Across the Spectrum of Renal Function: A Pooled Analysis of RCTs

BackgroundMineralocorticoid receptor antagonists (MRAs) are underused in patients with kidney dysfunction, and their efficacy among patients with chronic kidney disease (CKD) is uncertain. ObjectivesThe goal of this study was to analyze the efficacy and safety of steroidal MRAs across the spectrum of estimated glomerular filtration rates (eGFRs) in randomized controlled trials. The study included patients with heart failure (HF) or myocardial infarction and advanced CKD who participated in the RALES (Randomized Aldactone Evaluation Study), EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in the Americas, and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trials. MethodsThis study used individual patient data meta-analysis using Cox models stratified by trial with treatment-by-eGFR interaction terms. eGFR was recalculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula. ResultsA total of 12,700 patients were included, of whom 331 (2.6%) had an eGFR ≤30 mL/min/1.73 m2 (mean eGFR: 26.8 ± 3.2 mL/min/1.73 m2). Patients with advanced CKD had higher annualized event rates for all studied outcomes: placebo event rate for the composite of cardiovascular death or HF hospitalization was ∼3-fold higher in patients with eGFR ≤30 compared with those with eGFR >90 mL/min/1.73 m2: 41.6 vs 14.6 events per 100 person-years. MRAs (vs placebo) reduced the composite of cardiovascular death or HF hospitalization, but the effect was attenuated as eGFR decreased: the corresponding HRs by eGFR categories were: HR for >90 mL/min/1.73 m2: 0.62 (95% CI: 0.49-0.78); HR for 61-90 mL/min/1.73 m2: 0.69 (95% CI: 0.61-0.77); HR for 46-60 mL/min/1.73 m2: 0.84 (95% CI: 0.74-0.95); HR for 31-45 mL/min/1.73 m2: 0.79 (95% CI: 0.68-0.91); and HR for ≤30 mL/min/1.73 m2: 0.96 (95% CI: 0.70-1.32) (treatment-by-eGFR interaction P for trend = 0.033). Investigator-reported hyperkalemia and worsening renal function were more frequent (2- to 3-fold) among MRA users, and hyperkalemia was more frequent as eGFR decreased (treatment-by-eGFR interaction P for trend = 0.002). ConclusionsSteroidal MRAs reduced HF hospitalizations and mortality across a wide range of eGFR. However, declining benefit and worsening safety may limit their use in patients with lower eGFR, particularly those with levels ≤30 mL/min/1.73 m2.

Associations of body mass index with mortality in heart failure with preserved ejection fraction patients with ischemic versus non-ischemic etiology.

BackgroundObesity could paradoxically improve prognosis in patients with heart failure (HF), termed the “obesity paradox.” Whether HF etiology could modify the “obesity paradox” is still controversial. In the present study, we aimed to assess the relationship between obesity and death in patients with heart failure with preserved ejection fraction (HFpEF) with non-ischemic versus ischemic etiologies.MethodsWe analyzed 3,360 HFpEF patients from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Cox regression models were used to assess the association of obesity assessed by body mass index (BMI) with short-term and long-term death risk.ResultsOverweight and obesity were associated with a lower risk of long-term all-cause death in patients with non-ischemic HFpEF, even in those with class III obesity (adjusted HR: 0.61, 95% CI 0.38–0.97). However, in the ischemic subgroup, as obesity advanced, this paradoxical relationship was gradually attenuated and disappeared in class III obesity (adjusted HR: 0.93, 95% CI 0.56–1.57). Restricted cubic spline analyses confirmed the differential relationship of baseline BMI with risk of long-term death with a BMI higher than 30 kg/m2 in non-ischemic versus ischemic HFpEF. In the short-term follow-up, the beneficial effects of overweight and obesity on survival were consistently observed in all the BMI categories, with the nadirs of all-cause death risk at class III obesity category both in non-ischemic and ischemic subgroups.Conclusion“Obesity paradox” was evident both in non-ischemic and ischemic HFpEF during short-term follow-up, even in those with class III obesity. However, the beneficial effect of class III obesity disappeared during long-term follow-up in ischemic HFpEF.Clinical Trial Registration[https://clinicaltrials.gov], identifier [NCT00094302].

Usefulness of B-Type Natriuretic Peptide for Predicting the Risk of Stroke in Patients With Heart Failure With Preserved Ejection Fraction.

BackgroundB‐type natriuretic peptide (BNP) is a well‐known biomarker for prognosis in heart failure with patients with preserved ejection fraction. However, the clinical predictive ability of BNP for the risk of stroke in HFpEF is not clear.Methods and ResultsA total of 799 patients with HFpEF from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial were included. Association of baseline BNP with risk of stroke was assessed using the Cox proportional hazard model. The discriminatory ability of BNP was expressed using the C index. The improvement in 5‐year stroke prediction was assessed by C statistic, categorical net reclassification improvement index, and relative integrated discrimination improvement. A total of 34 (4.3%) patients among the 799 patients with HFpEF experienced stroke events over a median of 2.85 years of follow‐up. The stroke group showed a higher BNP level than the nonstroke group (375 pg/mL versus 241 pg/mL, respectively; P=0.006). Higher BNP levels were associated with increased risk of stroke after multivariable adjustment (hazard ratio, 3.29 [95% CI, 1.51–7.16]) and had a moderate performance for stroke prediction (C index, 0.67). Adding BNP to CHADS2/CHA2DS2‐VASc/R2CHADS2 scores improved their predictive value for stroke (CHADS2: C index, 0.67; BNP+CHADS2: C index, 0.77; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.0%; CHA2DS2‐VASc: C index, 0.64; BNP+CHA2DS2‐VASc: C index, 0.74; net reclassification improvement, 41.4%; integrated discrimination improvement, 2.2%; R2CHADS2: C index, 0.70; BNP+R2CHADS2: C index, 0.78; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.2%).ConclusionsBNP is associated with an increased risk of stroke in patients with HFpEF and may be a valuable biomarker for stroke prediction in HFpEF.

Prognostic Value of Time in Blood Pressure Target Range Among Patients With Heart Failure

BackgroundBlood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time. ObjectivesThis study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF). MethodsThe authors performed a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist) trial and the BEST (Beta-Blocker Evaluation of Survival Trial). Time in target range (TTR) for each patient was calculated using linear interpolation across the study period with the target range of systolic BP between 120 and 130 mm Hg. ResultsA total of 4,789 hypertensive patients (n = 1,654 from BEST and n = 3,135 from TOPCAT) were included. The cumulative incidences of primary endpoint (ie, cardiovascular death or HF hospitalization) were highest among the top quartile of TTR with a dose-dependent manner across quartiles (Ptrend <0.005). The top quartile of TTR was significantly associated with a lower risk of primary outcome using adjusted Cox regression model (HR: 0.71; 95% CI: 0.60-0.82), cardiovascular mortality (HR: 0.68; 95% CI: 0.55-0.84), HF hospitalization (HR: 0.70; 95% CI: 0.58-0.85), all-cause mortality (HR: 0.69; 95% CI: 0.58-0.83), and any hospitalization (HR: 0.76; 95% CI: 0.67-0.85). Further analyses using restricted cubic spline indicated a linear relationship between TTR and primary outcome. Similar patterns were observed in the individual trial. Sensitivity analyses generated consistent results while redefining target range as 110 to 130 mm Hg for systolic BP or 70 to 80 mm Hg for diastolic BP. ConclusionsTTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.

Time in Target Range for Systolic Blood Pressure and Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

BackgroundThe association between blood pressure control and clinical outcomes is unclear among patients with heart failure with preserved ejection fraction. Both too high and too low of systolic blood pressure (SBP) have been reported to be related to poor clinical prognosis. This study aimed to assess the association between time in SBP target range and adverse clinical events among patients with heart failure with preserved ejection fraction.Methods and ResultsThis study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, a randomized clinical trial that compared the efficacy and safety of spironolactone in patients with heart failure with preserved ejection fraction. Time in target range (TTR) was calculated using linear interpolation, with the target range of SBP defined as 110 to 130 mm Hg. The association between TTR with adverse outcomes was estimated using multivariable Cox regression to adjust for multiple confounders. Participants with greater TTR were younger, more likely to be White, had less comorbidities, and lower body mass index. After adjusting for multiple covariates including mean SBP, 1‐SD increment (38.3%) of TTR was significantly associated with a decreased risk of primary composite end point (hazard ratio [HR], 0.81 [0.73–0.90]), as well as a lower risk of all‐cause mortality (HR, 0.81 [0.73–0.90]), cardiovascular death (HR, 0.78 [0.68–0.90]), and heart failure hospitalization (HR, 0.85 [0.74–0.97]). Results were similar when participants were categorized by TTR groups. Subgroup analyses showed that the associations were more significant in young people than in the old (P interaction=0.028).ConclusionsIn patients with heart failure with preserved ejection fraction, greater time in SBP target range was statistically associated with a decreased risk of cardiovascular outcomes and mortality events beyond blood pressure level, especially among younger patients.

Spironolactone in Patients With an Echocardiographic HFpEF Phenotype Suggestive of Cardiac Amyloidosis: Results From TOPCAT

ObjectivesThis study investigated an enriched cohort of patients with heart failure and preserved ejection fraction (HFpEF) in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with an echocardiographic phenotype of cardiac amyloidosis. BackgroundThere is a high prevalence of increased interventricular septal (IVS) thickness and decreased mitral annular systolic (s′) velocity in cardiac amyloidosis. In addition, clinical trials of neurohormonal blockade are missing in this population. MethodsTOPCAT randomized patients with HFpEF to spironolactone or placebo therapy with a primary endpoint of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Patients with IVS and s′ velocity measurements were included, and adjusted Cox models assessed the effect of echocardiographic variables and spironolactone on the primary endpoint. ResultsAmong 590 patients, mean s′ velocity was 6.4 ± 2.1 cm/s and IVS thickness was 1.2 ± 0.2 cm. The enriched cohort with characteristics of cardiac amyloidosis (s′ velocity ≤6 cm/s and IVS thickness ≥1.2 cm) included 135 patients (23% of the cohort). After a median follow-up of 2.6 years (1.5-3.9 years), these patients had the worst prognosis (adjusted HR: 2.10; 95% CI: 1.26-3.50; P = 0.004). Both s′ velocity and IVS thickness were individually associated with the primary endpoint, and abnormalities in these parameters were additive as lower s′ velocity was particularly prognostic in those with greater IVS thickness (interaction: P = 0.013). Spironolactone was associated with improved outcomes in the overall cohort (P = 0.024), and patients in the enriched cohort had a benefit similar to that in other groups (interaction: P = 0.382). ConclusionsAn enriched subset of patients with structural and functional echocardiographic features of cardiac amyloidosis had the worst prognosis in the TOPCAT study, but they benefitted similarly from spironolactone therapy. Future studies of mineralocorticoid receptor antagonists in patients with cardiac amyloidosis are warranted.

Prognostic Value of Minimal Left Atrial Volume in Heart Failure With Preserved Ejection Fraction.

BackgroundMaximal left atrial (LA) volume is reported by most echocardiography laboratories and is associated with clinical outcomes in patients with heart failure (HF). Recent studies suggest that minimal LA volume may better reflect left ventricular filling pressure and may be more prognostic than maximal LA volume. This study assessed the prognostic value of indexed minimal LA volume (LAVImin) in patients with HF with preserved ejection fraction.Methods and ResultsWe assessed the relationship of LAVImin with a primary composite end point of cardiovascular death, aborted cardiac death, or HF hospitalization in 347 patients with HF with preserved ejection fraction enrolled from the Americas region in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We compared LAVImin with indexed maximal LA volume with respect to their prognostic values. In addition, we assessed if LA functional parameters provide additional prognostic information over LAVImin. During a median follow‐up of 2.5 years, 107 patients (31%) experienced a primary composite end point. LAVImin was associated with increased risk of a primary composite outcome (hazard ratio [HR], 1.35; 95% CI, 1.12–1.61) and HF hospitalization alone (HR, 1.42; 95% CI, 1.17–1.71) after adjusting for clinical confounders and ejection fraction. In contrast, indexed maximal LA volume was not related to the primary composite outcome, but related to HF alone (HR, 1.25; 95% CI, 1.02–1.54). In comparison with indexed maximal LA volume, LAVImin was significantly more prognostic for primary composite outcome (P for comparison=0.032). Both LA emptying fraction and LA strain were prognostic of primary outcome independent of LAVImin (all P<0.05).ConclusionsIn patients with HF with preserved ejection fraction, LAVImin was more predictive of cardiovascular outcome than indexed maximal LA volume, suggesting this measure may be more physiologically relevant and might better identify patients at high risk for cardiovascular events. LA functional parameters provide prognostic information independent of LAVImin.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT00094302.

Leukocyte count and the risk of adverse outcomes in patients with HFpEF

BackgroundInflammation is a key feature of heart failure including HFpEF. The leukocyte count is a marker of inflammation that is widely used in clinical practice. However, there is little available evidence for the relationship between leukocyte count and the outcomes of HFpEF.MethodsWe analyzed data from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. The primary outcome was all-cause mortality, the secondary outcome was composite cardiovascular events and hospitalization for heart failure. Multivariable Cox proportional hazard models were used to compare the risk profiles of patients with leukocyte quartiles, subgroup study divided by sex was also analyzed.ResultsThe present study included 2898 patients with HFpEF.429 deaths, 671 composite cardiovascular events and 386 hospitalization for heart failure occurred during a mean 3.4 years follow-up. The association between leukocyte count and adverse outcomes followed a U-shaped curve. After multivariable adjustment, the patients with the lowest leukocyte count (Q1) and the highest leukocyte count (Q4) faced higher risk of all-cause death(Q1 vs. Q2, adjusted HR: 1.439; 95% CI: 1.060–1.953, p = 0.020; Q4 vs. Q2, adjusted HR, 1.901; 95%CI: 1.424–2.539, p < 0.001). The subgroup analysis showed a consistent result in female but not male patients.ConclusionsThe association between leukocyte count and risk of adverse outcomes followed a U-shaped curve. Both higher and lower leukocyte count are associated with worse outcomes in patients with HFpEF, which may be attributed to the two sides of inflammation in cardiac remodeling.

Estimated Glomerular Filtration Rate Is Associated With an Increased Risk of Death in Heart Failure Patients With Preserved Ejection Fraction.

Background: Renal dysfunction is associated with adverse cardiovascular outcomes in patients with heart failure (HF), but its impact on patients with heart failure with preserved ejection fraction (HFpEF) remains unclear.Methods: 3,392 subjects of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial were assigned to two groups by estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2 or 30–59 ml/min/1.73 m2. The outcomes, including all-cause death, cardiovascular death and HF hospitalization, were examined by multivariable cox models.Results: Over a median follow-up of 3.4 ± 1.7 years, a total of 524 all-cause deaths, 334 cardiovascular deaths and 440 HF hospitalizations occurred. Compared with patients with eGFR ≥ 60 ml/min/1.73 m2, those with eGFR 30–59 ml/min/1.73 m2 were associated with an increased risk of the all-cause death [adjusted hazard ratio (HR), 1.47; 95% confidence interval (CI), 1.24–1.76; P < 0.001], cardiovascular death (adjusted HR, 1.53; 95% CI: 1.23–1.91; p < 0.001), and HF hospitalization (adjusted HR: 1.21; 95% CI: 1.00–1.47; p = 0.049) after multivariable adjustment for potential confounders.Conclusions: eGFR 30–59 ml/min/1.73 m2 was related to an increased risk of all-cause death, cardiovascular death and HF hospitalization in HFpEF patients.

Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function

BackgroundTreatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood. ObjectivesThe purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF. MethodsIn 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term. ResultsWRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF. ConclusionsAmong HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.

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 HeartFailure with an Aldosterone Antagonist) trial and the Penn HeartFailure 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.

Usefulness of CHADS2, R2CHADS2, and CHA2DS2-VASc scores for predicting incident atrial fibrillation in heart failure with preserved ejection fraction patients.

AimsCoexisting of atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) could increase the risk of mortality. In this study, we aimed to assess the values of the CHADS2, R2CHADS2, and CHA2DS2‐VASc scores for AF prediction in HFpEF patients.Methods and resultsWe performed a retrospective analysis on symptomatic HFpEF patients in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Associations of the CHADS2, R2CHADS2, and CHA2DS2‐VASc scores with the risk of incident AF in HFpEF patients without baseline AF (n = 2202) were assessed using the multivariable competing risk regression models. The discriminatory performances of these scores were calculated using the C‐index. During a median follow‐up of 3.3 years, the average incidence of AF was 1.80 per 100 patient‐years in HFpEF patients. When score was analysed as a continuous variable, per 1‐point increase in the CHADS2 (hazard ratio [HR] = 1.42, 95% confidence interval [CI]: 1.20–1.68, C‐index: 0.71), R2CHADS2 (HR = 1.25, 95% CI: 1.10–1.42, C‐index: 0.69), or CHA2DS2‐VASc (HR = 1.30, 95% CI: 1.16–1.46, C‐index: 0.70) scores was associated with an increased risk of incident AF. When score was analysed as a categorical variable, patients with CHADS2 ≥ 3 (HR = 2.62, 95% CI: 1.70–4.04), R2CHADS2 ≥ 3 (HR = 2.55, 95% CI: 1.56–4.17), or CHA2DS2‐VASc ≥ 4 (HR = 2.54, 95% CI: 1.59–4.07) had a higher risk of incident AF compared with the corresponding controls.ConclusionsOur data first suggest that the CHADS2, R2CHADS2, and CHA2DS2‐VASc scores could predict the risk of incident AF in HFpEF patients with modest predictive abilities.

Influence of polypharmacy on patients with heart failure with preserved ejection fraction: a retrospective analysis on adverse outcomes in the TOPCAT trial.

BackgroundPolypharmacy is common in heart failure (HF), whereas its effect on adverse outcomes in patients with HF with preserved ejection fraction (HFpEF) is unclear.AimTo evaluate the prevalence, prognostic impacts, and predictors of polypharmacy in HFpEF patients.Design and settingA retrospective analysis performed on patients in the Americas region (including the US, Canada, Argentina, and Brazil) with symptomatic HF and a left ventricular ejection fraction ≥45% in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, an international, randomised, double-blind, placebo-controlled study conducted during 2006–2013 in six countries.MethodPatients were categorised into four groups: controls (<5 medications), polypharmacy (5–9 medications), hyperpolypharmacy, (10–14 medications), and super hyperpolypharmacy (≥15 medications). The outcomes and predictors in all groups were assessed.ResultsOf 1761 participants, the median age was 72 years; 37.5% were polypharmacy, 35.9% were hyperpolypharmacy, and 19.6% were super hyperpolypharmacy, leaving 7.0% having a low medication burden. In multivariable regression models, three experimental groups with a high medication burden were all associated with a reduction in all-cause death, but increased risks of HF hospitalisation and all-cause hospitalisation. Furthermore, several comorbidities (dyslipidemia, thyroid diseases, diabetes mellitus, and chronic obstructive pulmonary disease), a history of angina pectoris, diastolic blood pressure <80 mmHg, and worse heart function (the New York Heart Association functional classification level III and IV) at baseline were independently associated with a high medication burden among patients with HFpEF.ConclusionA high prevalence of high medication burden at baseline was reported in patients with HFpEF. The high medication burden might increase the risk of hospital readmission, but not the mortality.

Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension.

BackgroundResistant hypertension is a salt‐retaining condition possibly attributable to inappropriate aldosterone secretion.Methods and ResultsThis study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin‐angiotensin system blocker (angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53–0.91; P=0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83–1.20; P=0.97). There was a significant interaction between spironolactone use and resistant hypertension (P=0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only.ConclusionsSpironolactone may be an effective add‐on medication for patients with HFpEF with resistant hypertension taking angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.