Mentz, Robert J.

Background: Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether the extent of coronary artery stenosis differs by HF type or prognosis for patients admitted with acute decompensated heart failure (ADHF) is uncertain. Methods: The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of adjudicated HF in 4 US areas from 2005-2014. Medical histories were abstracted from the hospital record. Obstructive CAD was defined as > 49% stenosis in the left main coronary artery or >74% stenosis in the other major coronary arteries. Associations between obstructive CAD and 28-day mortality were analyzed separately for heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), adjusting for age, race, sex, year of admission, and coronary revascularization procedures. All analyses were weighted by the inverse of the sampling probability. Results: A total of 5115 patients admitted with ADHF underwent coronary angiography during the hospital visit (mean age = 72, 45% women, 28% Black, 30% HFpEF). Obstructive CAD was more prevalent with HFrEF ( Figure 1 ), whether at the left main coronary artery (16% vs 12%), left anterior descending artery (50% vs 35%), left circumflex artery (42% vs 34%), right coronary artery (45% vs 34%), or multiple coronary vessels (47% vs 34%). A similar proportion of patients with obstructive CAD underwent revascularization, irrespective of HF type (HFrEF: 55%, HFpEF: 61%). After adjustments, obstructive CAD (in any vessel) was associated with higher 28-day mortality, both for HFrEF (OR: 3.21; CI: 1.91 - 5.97) and HFpEF (OR: 3.62; 95% CI: 1.43 - 9.18) with no significant interaction by HF type ( P -interaction = 0.9). Conclusion: Patients hospitalized with ADHF and coexisting obstructive CAD are at greater risk of short-term mortality, irrespective of the HF type, warranting the need for effective interventions as well as secondary preventive measures in this population.

Background Associations between depression, incident heart failure (HF), and mortality are well documented in predominately White samples. Yet, there are sparse data from racial minorities, including those who are women, and depression is underrecognized and undertreated in the Black population. Thus, we examined associations between baseline depressive symptoms, incident HF, and all‐cause mortality across 10 years. Methods and Results We included Jackson Heart Study (JHS) participants with no history of HF at baseline (n=2651; 63.9% women; median age, 53 years). Cox proportional hazards models tested if the risk of incident HF or mortality differed by clinically significant depressive symptoms at baseline (Center for Epidemiological Studies–Depression scores ≥16 versus <16). Models were conducted in the full sample and by sex, with hierarchical adjustment for demographics, HF risk factors, and lifestyle factors. Overall, 538 adults (20.3%) reported high depressive symptoms (71.0% were women), and there were 181 cases of HF (cumulative incidence, 0.06%). In the unadjusted model, individuals with high depressive symptoms had a 43% greater risk of HF ( P =0.035). The association remained with demographic and HF risk factors but was attenuated by lifestyle factors. All‐cause mortality was similar regardless of depressive symptoms. By sex, the unadjusted association between depressive symptoms and HF remained for women only ( P =0.039). The fully adjusted model showed a 53% greater risk of HF for women with high depressive symptoms ( P =0.043). Conclusions Among Black adults, there were sex‐specific associations between depressive symptoms and incident HF, with greater risk among women. Sex‐specific management of depression may be needed to improve cardiovascular outcomes.

Abstract Introduction The prevalence and outcomes of polyvascular disease (PVD) in patients admitted with acute decompensated heart failure (ADHF) have not been previously reported, nor is it known whether associations differ for heart failure (HF) with reduced vs. preserved ejection fraction (HFrEF vs HFpEF, respectively). Purpose To investigate the relationship between atherosclerotic involvement of multiple arterial territories and mortality in patients hospitalized with ADHF. Methods The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of adjudicated heart failure in 4 US areas from 2005–2014, with events verified by physician review. Medical histories were abstracted from the hospital record. PVD was defined by coexisting disease in ≥2 arterial beds, identified by prevalent coronary artery disease, peripheral arterial disease, and cerebrovascular disease. Mortality hazards of PVD vs. no PVD were analyzed separately for HFpEF and HFrEF, with adjustment for age, race, sex, year of admission and geographic region. All analyses were weighted by the inverse of the sampling probability. Results Of 24,936 ADHF hospitalizations (52% female, 32% Black, mean age 75 years), 19% had PVD (22% among HFrEF hospitalizations, 17% among HFpEF hospitalizations), Figure 1. There was an increasing trend in 1-year mortality with 0, 1 and ≥2 arterial bed involvement, both for patients with HFrEF (29% to 32% to 38%; P-trend=0.0006) and HFpEF (26% to 32% to 37%; P-trend &lt;0.0001). After adjustments, PVD was associated with a 20% higher hazard of 1-year mortality in patients with HFrEF (HR=1.23; 95% CI: 1.06–1.44) and a 30% higher hazard in patients with HFpEF (HR=1.33; 95% CI: 1.09–1.63), with no significant interaction by HF type (P-interaction = 0.5). Conclusion Patients hospitalized with ADHF and coexisting PVD have an increased risk of death, irrespective of HF type. Clinical attention should be directed toward PVD, with secondary prevention strategies enacted to improve the prognosis of this vulnerable population. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health Distributions of arterial diseaseTrends in 1-year mortality outcomes

Background: The Kansas City Cardiomyopathy Questionnaire (KCCQ) has been psychometrically evaluated in multiple heart failure (HF) populations, but the comparability of its psychometric properties between men and women is unknown. Methods: Data from 3 clinical trials (1 in stable HF with preserved ejection fraction, 1 each in stable and acute HF with reduced ejection fraction) and 1 prospective cohort study (stable HF with reduced ejection fraction), incorporating 6773 men and 3612 women with HF, were used to compare the construct validity, internal and test-retest reliability, ability to detect change, predict mortality and hospitalizations and minimally important differences between the 2 sexes. Interactions of the KCCQ overall summary and subdomain scores by sex were independently examined. Results: The KCCQ-Overall Summary score correlated well with New York Heart Association functional class in both sexes across patients with stable (correlation coefficient: −0.40 in men versus −0.49 in women) and acute (−0.37 in men versus −0.34 in women) HF. All KCCQ subdomains demonstrated concordant relationships with relevant comparison standards with no significant interactions by sex in 19 of 21 of these construct validity analyses. All KCCQ scores were equally predictive and other psychometric evaluations showed similar results by sex: test-retest reliability (intraclass correlation coefficient 0.94 in men versus 0.92 in women), responsive to change (standardized response mean 1.01 in both sexes), as were the minimally important differences and internal reliability. Conclusions: The psychometric properties of the KCCQ, in terms of validity, prognosis, reliability, and sensitivity to change, are comparable in men and women with HF with preserved ejection fraction and HF with reduced ejection fraction.

Introduction: Despite the use of different definitions for worsening heart failure (WHF) in prior clinical trials and registries, an in-hospital WHF event has consistently been associated with worse patient outcomes. WHF is being considered as a potential endpoint to support drug approval. We combined patients from two acute HF trials conducted by the HF Network (ROSE-AHF and DOSE-AHF) to understand how different WHF definitions are associated with event rates. Methods: WHF was defined as persistent or worsening HF requiring rescue therapy including IV vasoactive agents, ultrafiltration, or mechanical support over 72 hours after randomization in ROSE and also included additional open label loop or thiazide diuretic in DOSE. We assessed the relationship between WHF and the composite endpoint (CE) of re-hospitalization, emergency room visits for HF and mortality through 60 days. We also assessed for a differential relationship of WHF from 0-24 hours, 24-48 hours and 48-72 hours post-randomization. Results: The overall incidence of WHF was 14.6% (24.1% in DOSE and 6.3% in ROSE). Patients who developed WHF had lower baseline systolic blood pressure, less peripheral edema and higher BUN. In the combined dataset, WHF was associated with an increase in the CE (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.11-2.42; p-value 0.01). However, the association between WHF and 60-day outcomes was significant in ROSE but not in DOSE (Table). The development of WHF between 48-72 hours compared with 0-24 hours or 24-48 hours was associated with improved outcomes ([HR] 0.48, 95% CI 0.27 - 0.88, p-value 0.02 and [HR] 0.45, 95% CI 0.26 - 0.78, p-value 0.004, respectively). Conclusions: A WHF definition that incorporated intensification of diuretics increased the event rate but was not associated with worse 60-day outcomes. The timing of a WHF event also had a differential association with outcomes. These data support the use of a standardized WHF definition in clinical trials.

Abstract Aims Associations between growth differentiation factor-15 (GDF-15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP-1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF-15 and change in GDF-15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF-15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF-15 were more likely to be male and have more co-morbidities. After adjustment, an increase in GDF-15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF-15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF-15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF-15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF-15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF-15 trajectory in informing risk of heart failure disease progression.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS-HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter-quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P &lt; 0.001), greater burden of co-morbidities, higher intravascular pressures estimated on physical examination (elevated jugular venous pressure: 50% vs. 24.7%, P &lt; 0.001), poorer renal function (creatinine: 1.2 mg/dL [IQR 0.9, 1.5] vs. 1 mg/dL [IQR 0.8, 1.3], P = 0.003), and lower peak VO2 (adjusted mean difference −1.04 mL/kg/min, 95% confidence interval [−1.71, −0.37], P &lt; 0.003). Among hospitalized patients, despite greater in-hospital fluid/weight loss in the ≥moderate oedema group, there was no difference in the improvement in dyspnoea by the visual analogue scale or well-being visual analogue scale from baseline to 3–4 days and no statistically significant difference in the rate of 60 day rehospitalization/death (adjusted hazard ratio 1.44, 95% confidence interval [0.87, 2.39], P = 0.156). Conclusions Patients with HFpEF and oedema display higher body mass, greater burden of co-morbidities, and more severe exercise intolerance, but clinical responses to treatment appear similar. Further research is required to better understand the nature of volume distribution in different HFpEF phenotypes.

Background: The FIGHT (Functional Impact of GLP-1 [glucagon-like peptide-1] for Heart Failure Treatment) trial randomized 300 patients with heart failure with reduced ejection fraction (HFrEF) and a recent hospitalization for heart failure to liraglutide versus placebo. While there was no difference in the primary outcome (rank score of time to death, time to rehospitalization for heart failure, and change in NT-proBNP [N-terminal pro-B-type natriuretic peptide]), there was a significant increase in cystatin C among patients randomized to liraglutide raising concern of adverse renal outcomes. We performed a post hoc analysis of FIGHT to investigate whether liraglutide was associated with worsening renal function (WRF). Methods: The relationship between randomization to liraglutide and WRF was evaluated using logistic regression models. Two hundred seventy-four patients (91%) had complete data to assess for WRF defined as: increase in SCr ≥0.3 mg/dL, or ≥25% decrease in estimated glomerular filtration rate, or an increase in cystatin C ≥0.3 mg/L from baseline to 180-days. Results: Patients with WRF (n=113, 41%), compared with those without, were older, had more comorbidities, and lower utilization of guideline-directed medical treatment. Logistic regression models showed that age and baseline cystatin C levels were associated with WRF. In adjusted models, liraglutide was not associated with excess risk of WRF compared with placebo (odds ratio, 1.02 [95% CI, 0.62–1.67]). There was also no difference in the rank score when WRF was added as a fourth-tier outcome. Conclusions: Liraglutide was not associated with WRF among patients with HFrEF and a recent hospitalization for heart failure. These data support the relative renal safety profile of liraglutide among patients with HFrEF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01800968.

Background We sought to study the prevalence of high‐sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction ( HF p EF ). Methods and Results A post hoc analysis utilized data from HF p EF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS ‐ HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HF p EF , and RELAX (Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HF p EF . High‐sensitivity troponin I (hs‐TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs‐TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs‐TnI and cardiac structure and function were assessed. The association between hs‐TnI and a 60‐day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HF p EF and hs‐TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients ( P <0.001). The prevalence of elevated hs‐TnI (>99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow‐up. HF p EF patients with a hs‐TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs‐TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00‐1.43; P =0.042). Conclusions Hs‐TnI is commonly elevated among both hospitalized and ambulatory patients with HF p EF . Increased hs‐TnI levels are associated with worse cardiac structure and increased risk of adverse events.

Abstract Heart failure (HF) is an increasingly prevalent condition with a very high symptom burden. To address challenges faced by palliative care clinicians, we assembled a team of experts to provide high-yield tips for the management of these patients. Prognosis is unpredictable in HF and many patients and physicians overestimate survival. Ejection fraction, notably, is not predictive of prognosis. It is important to have thorough discussions about implantable cardioverter defibrillators in terminally ill HF patients. Diuresis is the mainstay of managing volume overload and dyspnea in these patients and it is important to be aggressive and creative to achieve symptom relief. However, HF patients have a high burden of comorbidities and have many symptoms beyond dyspnea as well. Management in hospice remains challenging for these patients, with a significant risk for readmission to the hospital. Almost a quarter of HF patients discharged to hospice from the hospital die in less than three days.