Long-term Heart Failure Outcomes Research Articles

Supra-normal and mildly reduced ejection fraction in women -An overlooked vulnerable subpopulation in heart failure

BackgroundRecently, patients with supra-normal left ventricular ejection fraction (snEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. MethodsThe multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3943 patients (age 77 years; 40.1% female) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF. The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. ResultsIn HFmrEF, implementation of guideline-directed medical therapy (GDMT) such as the combination of renin-angiotensin-system inhibitor (RASi) and β-blocker at discharge was significantly lower in women than men even after adjustment for covariates (p = 0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint showing higher event rate in HFmrEF and HFsnEF in women, but such relationship was not observed in men (p for interaction = 0.037). ConclusionsIn women, mrEF and snEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for further exploration, which might lead to creation of sex-specific guidelines to optimize HF management.

Effect of short-term cardiac function changes after cardiac resynchronization therapy on long-term prognosis in heart failure patients with and without diabetes.

The relationship between short-term cardiac function changes and long-term outcomes in heart failure (HF) patients undergoing cardiac resynchronization therapy (CRT) remains uncertain, especially when stratified by diabetes status. This study aims to assess the association between short-term cardiac function changes and outcomes such as all-cause mortality and HF hospitalization in patients undergoing CRT, stratified by diabetes status. This is a cohort longitudinal retrospective study. A total of 666 HF patients, treated with CRT between March 2007 and March 2019, were included in this study. Among them, 166 patients (24.9%) were diagnosed with diabetes. Cardiac function was assessed at baseline and again at 6 months, incorporating evaluations of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left atrial diameter (LAD), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and QRS duration. The QRS duration represents the time required for a stimulus to spread through the ventricles (ventricular depolarization). The primary endpoints of the study were all-cause mortality and HF-related hospitalization. During a median follow-up of 2.51 years, 172 (25.8%) patients died and 197 (29.6%) were hospitalized for HF. Changes in LVEF, LVEDD, and LAD within 6 months had similar effects on adverse outcomes in both diabetic and nondiabetic patients. However, the presence of diabetes significantly modified the association between changes in NT-proBNP and QRS duration and adverse outcomes. Short-term changes in NT-proBNP and QRS duration were positively associated with all-cause mortality and HF hospitalization in patients without diabetes. However, the relationship between short-term changes in NT-proBNP and QRS duration and adverse outcomes was non-linear in diabetic patients. Improvement of cardiac function after CRT implantation can reduce long-term risk of all-cause mortality and HF hospitalization in HF patients. However, the presence of diabetes may affect the association between short-term changes in NT-proBNP and QRS duration and adverse outcomes.

The HFFI, a new frailty index for assessing long-term outcomes in heart failure

Abstract Introduction Patients hospitalized due to heart failure (HF) compose a heterogeneous population whose prognosis is difficult to forecast. Frailty is a well-recognized prognostic marker in multiple chronic diseases, including HF; however, frailty evaluation is often subjective and standardized and objective prediction models are lacking. We aimed to evaluate if an objective and simple index – Heart Failure Frailty Index (HFFI)– can predict long-term outcomes in this population. Methods A retrospective analysis of 258 patients admitted to a Cardiology ward due to HF was performed. The variables albumin, C-reactive protein levels, age and body mass index (BMI) were selected for frailty assessment. After attributing points for each variable, according to odds ratio on univariate analysis, the HFFI was calculated (range 0–8), resulting from the sum of the points attributed to each variable. Kaplan-Meyer and Cox-regression analysis were performed to evaluate HFFI association with 24-month mortality (24MM) and 24-month composite endpoint of rehospitalization or death (24MH). Results Mean patient age was 75 (±11) years; 51% were men. 45.7% had atrial fibrillation, 15.9% hat history of acute myocardial infarction, 67.8% had hypertension. Mean LVEF was 47% (±17). A LVEF <40% was present in 40% of patients. 24MM was 11.5% and 24 MH was 58%. Patients were considered frail if they had an HFFI ≥3. Kaplan-Meyer curve analysis revealed a significantly lower median time to 24MM in frail patients, as assessed by HFFI, comparing to non-frail patients (585±33 days vs 697±12 days, mortality rate: 25.4% vs 5.7%, χ2=18.156, p<0.001). There was also a significantly lower median time to 24MH in frail patients (336±34 days vs 449±24 days, combined endpoint rate: 76.1% vs 50.3%, χ2=10.884, p=0.001). Cox regression analysis demonstrated that HFFI independently predicts 24MM (HR: 1.364, p=0.002) and 24MH (HR: 1.106, p=0.035), even after adjustment for other prognostic markers, such as history of atrial fibrillation, previous myocardial infarction, diabetes and natriuretic peptides serum level at index event. Conclusion HFFI is a simple and objective frailty index correlated with 24MM and 24MH, being an independent prognostic marker in this population. Its use may help to identify patients with a high risk of mortality or readmission, in need of specialized care. Funding Acknowledgement Type of funding sources: None.

Impact of aortic regurgitation on long-term outcomes in heart failure with preserved ejection fraction

Abstract Background Aortic Regurgitation (AR) may aggravate the clinical course in patients with heart failure and preserved ejection fraction (HFpEF) by increasing filling pressures and triggering LV remodelling. Objective To assess AR's prevalence and long-term prognostic implications in patients with HFpEF. Methods The study population consisted of 458 consecutive patients (age 77.5±9.2 y, 57.9% females) hospitalized with de novo or worsened HFpEF. Patients with more than moderate aortic and/or mitral valve disease were excluded. Data on cardiovascular death, HF re-hospitalization and their composite (MACE) were collected. Results Out of 309 (67.5%) patients with any AR, 156 (34.0%) and 153 (33.5%) had mild-AR and moderate-AR, respectively. The remaining 149 (32.5%) individuals had no-AR. Patients with versus without AR were significantly older with larger LV and LA volumes and a higher prevalence of diastolic dysfunction (all p<0.05). During a median follow-up of 33±25 months, a total of 114 patients (24.9%) died from cardiovascular causes, 126 patients (27.5%) were re-hospitalized for HF, while 272 (59.4%) had the composite endpoint (MACE). In multivariable Cox regression analysis, any AR emerged as an only independent predictor of MACE (HR=1.90, 95% CI 1.26–2.87, p=0.002). Mild-AR and Moderate AR increased the risk of MACE by 77% and 92%, respectively, compared to the No-AR (Figure). Conclusions In patients with HFpEF, mild-to-moderate AR is highly prevalent, and it seems to identify individuals with worse long-term outcomes. This suggests that even mild AR should be considered a high-risk prognostic marker in patients with HFpEF. Funding Acknowledgement Type of funding sources: None.

Chronotropic index and long-term outcomes in heart failure with preserved ejection fraction

Introduction and objectivesLittle is known about the usefulness of heart rate (HR) response to exercise for risk stratification in heart failure with preserved ejection fraction (HFpEF). Therefore, this study aimed to assess the association between HR response to exercise and the risk of total episodes of worsening heart failure (WHF) in symptomatic stable patients with HFpEF. MethodsThis single-center study included 133 patients with HFpEF (NYHA II-III) who performed maximal cardiopulmonary exercise testing. HR response to exercise was evaluated using the chronotropic index (CIx) formula. A negative binomial regression method was used. ResultsThe mean age of the sample was 73.2± 10.5 years; 56.4% were female, and 51.1% were in atrial fibrillation. The median for CIx was 0.4 [0.3-0.55]. At a median follow-up of 2.4 [1.6-5.3] years, a total of 146 WHF events in 58 patients and 41 (30.8%) deaths were registered. In the whole sample, CIx was not associated with adverse outcomes (death, P=.319, and WHF events, P=.573). However, we found a differential effect across electrocardiographic rhythms for WHF events (P for interaction=.002). CIx was inversely and linearly associated with the risk of WHF events in patients with sinus rhythm and was positively and linearly associated with those with atrial fibrillation. ConclusionsIn patients with HFpEF, CIx was differentially associated with the risk of total WHF events across rhythm status. Lower CIx emerged as a risk factor for predicting higher risk in patients with sinus rhythm. In contrast, higher CIx identified a higher risk in those with atrial fibrillation.

Longitudinal trajectories in renal function before and after heart failure hospitalization among patients with heart failure with preserved ejection fraction in the PARAGON-HF trial.

Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes. In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomerular filtration rate (eGFR); (ii) development of end-stage renal disease; or (iii) death attributable to renal causes. A total of 2306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan versus valsartan was similar between patients with (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.24-0.76) and without (HR 0.63; 95% CI: 0.33-1.18; pinteraction =0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (pinteraction =0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p < 0.001). A change in the rate of decline of eGFR trajectory was observed 12 months preceding a HF hospitalization, and continued in the post-discharge window to 12 months following hospitalization. Heart failure hospitalization denotes increased risk for kidney disease progression which continues following recovery from HF decompensation in patients with HF with preserved ejection fraction. PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), ClinicalTrials.gov NCT01920711.

Behavioral economics strategies for promoting adherence to treatment in heart failure patients

Abstract Heart failure (HF) is characterized by an increased risk of both fatal and nonfatal adverse cardiovascular events, which required life-long and costly treatment. At the same time every cardiology practitioner is well aware, that despite huge efforts on patient's education there remains a substantial part of patients who do not always make rational choices regarding their treatment. Patient's knowledge does not always translate into adherence, so we must find ways to minimize the intent-behavior gap to improve the efficacy of HF treatment. We presume that behavioral economics can provide us with tools that will promote positive present behavior of patients. The purpose of the study was to examine the utility of behavioral economics-related concepts in understanding long-term treatment strategy in heart failure patients and acute heart failure survivors. Methods We performed an open prospective study involving male patients with both chronic and acute heart failure (CHF n=65 and AHF n=54). Involved patients were surveyed on symptom severity, behavioral economics “parameters”. Cognitive complexity was measured via “real life” case simulations. We assessed stress and depression with HADS and Zung's scales serially: on admission, 3d day of hospitalization and day before discharge. In patients with AHF, first assessment was performed after clinical stabilization. The primary outcomes were set as an adherence to prescribed medication assessed 6 and 36 months after discharge, rehospitalization due to cardiovascular reasons and self-assessed well-being. Results We observed opposite patterns of stress dynamics in CHF and AHF groups. AHF patients demonstrated significant reduction of stress level on the 3d day since admission: 9.0 (7.1; 9.9) vs 6.4 (5.7; 7.4) units, p=0.037, with further increase at discharge, while in CHF patients there was tendency to significant change in parameter was absent. Patients who survived AHF demonstrated higher 6 month adherence to prescribed medication (62.9% vs 49.2%, p=0.047), at the same time there was the strong positive correlation between medication's price and self-induced therapy interruption (R=0.74, p&amp;lt;0.05). Both AHF and CHF reported financial planning as the major contributor for decision making in “real life” cases. Surprisingly in study population self-assessed well-being did not correlated with rehospitalization rate. Parameters that were significantly associated with CV rehospitalization included symptoms at admission (OR 2.1 CI 1.4; 3.2, p=0.002), regularly saving money (OR =2.7 CI 1.9; 4.6, p=0.001) and stress level at discharge (OR 1.6 CI 1.1; 2.4, p=0.027). Conclusion Received results may be useful to identify heart failure patients at higher risk of self-induced treatment interruption. These patients could be offered focused support and counseling designed to enhance adherence to prescribed medication in order to improve long-term heart failure outcomes. Funding Acknowledgement Type of funding sources: None.

Clinical Heart Failure Among Patients With and Without Severe Mental Illness and the Association With Long-Term Outcomes.

Patients with severe mental illness (SMI) including schizophrenia, bipolar disorder, and severe depression have earlier onset of cardiovascular risk factors, predisposing to worse future heart failure (HF) compared with the general population. We investigated associations between the presence/absence of SMI and long-term HF outcomes. We identified patients with HF with and without SMI in the Duke University Health System from 2002 to 2017. Using multivariable Cox regression, we examined the primary outcome of all-cause mortality. Secondary outcomes included rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation. We included 20 906 patients with HF (SMI, n=898; non-SMI, n=20 008). Patients with SMI presented clinically 7 years earlier than those without SMI. We observed an interaction between SMI and sex on all-cause mortality (P=0.002). Excess mortality was observed among men with SMI compared with men without SMI (hazard ratio, 1.36 [95% CI, 1.17-1.59]). No association was observed among women with and without SMI (hazard ratio, 0.97 [95% CI, 0.84-1.12]). Rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation were similar between patients with and without SMI (6.1% versus 7.9%, P=0.095). Patients with SMI receiving these procedures for HF experienced poorer prognosis than those without SMI (hazard ratio, 2.12 [95% CI, 1.08-4.15]). SMI was associated with adverse HF outcome among men and not women. Despite equal access to procedures for HF between patients with and without SMI, those with SMI experienced excess postprocedural mortality. Our data highlight concurrent sex- and mental health-related disparities in HF prognosis, suggesting that patients with SMI, especially men, merit closer follow-up.

Loop Diuretic Prescription and Long-Term Outcomes in Heart Failure: Association Modification by Congestion

BackgroundThe effect of loop diuretics on clinical outcomes in heart failure has not been evaluated in randomized controlled trials. In hospitalized patients with heart failure, a discharge loop diuretic prescription has been shown to be associated with improved 30-day outcomes, which appears to be more pronounced in subgroups with congestion. In the current study, we examined these associations and association modifications during longer follow-up. MethodsWe assembled a propensity score-matched cohort of 2191 pairs of hospitalized heart failure patients discharged with, vs without, a prescription for loop diuretics, balanced on 74 baseline characteristics (mean age 78 years; 54% women; 11% African American). ResultsHazard ratio (HR) and 95% confidence interval (CI) for 6-year combined endpoint of heart failure readmission or all-cause mortality was 1.02 (0.96-1.09). HRs and 95% CIs for this combined endpoint in patients with no, mild-to-moderate, and severe pulmonary rales were 1.19 (1.07-1.33), 0.95 (0.86-1.04), and 0.77 (0.63-0.94), respectively (P for interaction, < .001). Respective HRs (95% CIs) for no, mild-to-moderate, and severe lower extremity edema were 1.16 (1.06-1.28), 0.94 (0.85-1.04), and 0.71 (0.56-0.89; interaction P < .001). ConclusionsThe association between a discharge loop diuretic prescription and long-term clinical outcomes in hospitalized patients with heart failure is modified by admission congestion with worse, neutral, and better outcomes in patients with no, mild-to-moderate, and severe congestion, respectively. If these findings can be replicated, congestion may be used to risk-stratify patients with heart failure for potential optimization of loop diuretic prescription and outcomes.

Sex differences in ventricular remodeling and long-term heart failure outcomes following acute coronary syndrome

Abstract Background Compared with men, women are at increased risk of heart failure hospitalization following acute coronary syndrome (ACS). Purpose We sought to determine whether this increased hazard was associated with differing patterns in left ventricular (LV) remodeling over the first 12 months after ACS. Methods In a prospective multi-centre observational cohort study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months following the index event. Heart failure hospitalisation events were captured over a median 4.8 (IQR 3.4–6.5) years and relative risk compared between women and men using a multivariable Cox model adjusted for baseline demographics (age and systolic blood pressure) and echocardiographic variables (LV end diastolic and end systolic volumes, LV ejection fraction, interventricular septal wall thickness, and E/e') captured at baseline and 12 months. Results The 609 (28.5%) women were older (mean [SD] age 70 [12] versus 65 [12] years), had higher systolic blood pressure, demonstrated smaller increases in peak myocardial biomarkers, and were less likely to undergo coronary revascularization during the index admission (41.9% versus 62.0%; p&amp;lt;0.001 for all). After indexing for body surface area, women had smaller LV end diastolic and end systolic volumes, greater LV ejection fractions, and greater septal wall thickness and diastolic filling pressure estimates (E/e' 14 versus 11; p&amp;lt;0.001 for all). Diastolic volumes further diverged at 12 months (p=0.05) and septal wall thickness increased compared with men (p=0.016). In unadjusted and adjusted analyses women were at increased risk of future heart failure hospitalization (unadjusted HR 1.5, 95% CI 1.2–1.9, adjusted HR 1.6, 95% CI 1.1–2.4). Conclusions Women experience a more concentric remodeling pattern over the 12 months following ACS. Women remain at increased risk of long-term heart failure hospitalization after accounting for clinical and echocardiographic characteristics. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation of New Zealand, New Zealand Health Research Council

Age-related differences in ventricular remodeling and long-term heart failure outcomes following acute coronary syndrome

Abstract Background Older patients are at increased risk of heart failure hospitalization following acute coronary syndrome (ACS). Purpose We sought to determine whether this increased hazard was related to differing patterns in left ventricular (LV) remodeling over the first 12 months after ACS. Methods In a prospective multi-centre observational cohort study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months following the index event. Long-term heart failure hospitalisation events were captured for a median 4.8 (IQR 3.4–6.5) years and the relative risk compared between individuals ≤65 years and those &amp;gt;65 years using a multivariable Cox model adjusted for baseline clinical (sex, blood pressure, coronary revascularisation) and echocardiographic (LV end diastolic and end systolic volumes, LV ejection fraction, interventricular septal wall thickness, and E/e') variables recorded at baseline and 12 months. Results The 1177 (55%) participants who were &amp;gt;65 years were more likely to be women (34% versus 22%), had higher blood pressure, were more likely to present with non-ST elevation ACS, demonstrated smaller increases in peak myocardial biomarkers and were less likely to undergo coronary revascularization during the index admission (43.2% versus 72.3%; p&amp;lt;0.001 for all comparisons). At the 1 month visit, after indexing for body surface area, older patients had similar LV end diastolic but larger end systolic volumes (p=0.029), lower LV ejection fractions, and greater left ventricular mass and diastolic filling pressure estimates (E/e' 14 versus 10; p&amp;lt;0.001 for all) compared with the young. Systolic volumes appeared to further diverge at 12 months (p=0.064) however LV mass did not change in either group. In unadjusted analysis older patients were at increased risk of future heart failure hospitalization (HR 4.1, 95% CI 3.2–5.3). This increased risk persisted after adjustment for differences in baseline clinical and echocardiography data, and LV remodeling (adjusted HR 2.4, 95% CI 1.5–3.9). Conclusions Older patients experience a more eccentric remodeling pattern over the 12 months following ACS. Older individuals remain at increased risk of long-term heart failure hospitalization after accounting for clinical and echocardiographic characteristics. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): New Zealand Heart Foundation, New Zealand Health Research Council

Role of angiotensin peptides in risk stratification and prognostication for heart failure: focus on plasma Ang 1–7/Ang II ratio

Abstract Background ACE2 and Ang 1–7 are endogenous negative regulators of the renin-angiotensin system (RAS) exerting cardioprotective effects in models of heart failure (HF). Recombinant ACE2 markedly increased plasma Ang 1–7 and lowered Ang II levels in clinical trials. Elevated plasma ACE2 activity is associated with adverse outcomes in HF patients. However, the direct effects of systemic and tissue ACE2 activation on angiotensin peptides in relation to long-term HF outcomes has yet to be examined. Purpose To generate insights into the ACE2 mediated cardioprotective arm through the relative levels of its substrates and products using the plasma Ang 1–7/Ang II ratio, and assess its prognostic utility in HF patients. Methods 110 HF patients were prospectively enrolled from outpatient clinics and the emergency department. Comprehensive circulating and equilibrium levels of plasma angiotensin peptides were assessed using novel liquid chromatography-mass spectrometry/mass spectroscopy techniques. Plasma aldosterone, BNP, active renin activity and clinical profiles were captured at baseline. Patients were stratified into above and below median cohorts based on equilibrium and circulating levels of Ang 1–7/Ang II ratio, as a surrogate for ACE2 functionality. During a median follow-up of 5.1±0.8 years, composite clinical outcomes were assessed through all-cause in-patient hospitalizations and mortality. Results Circulating and equilibrium angiotensin peptide levels strongly correlated in our patient cohort. All-cause mortality for HF patients with equilibrium Ang 1–7/Ang II ratios above the median showed higher survival rates compared to below median patients (76.4% vs. 50.9%; p=0.004); similar results were observed for circulating Ang 1–7/Ang II ratios (72.7% vs. 54.5%; p=0.041). Adjusting for covariates, elevated equilibrium (HR: 0.24; 95% CI: 0.09 to 0.69; p=0.008) and circulating (HR: 0.35; 95% CI: 0.13 to 0.94; p=0.036) Ang 1–7/Ang II ratios was associated with improved survival. Lower hospitalization duration was also associated with elevated equilibrium (p&amp;lt;0.001) and circulating (p=0.023) Ang 1–7/Ang II ratios. In nested models, net reclassification analysis showed considerable improvement in risk prediction for all-cause mortality at 5 years provided by both the equilibrium (+45.0% [95% CI: 7.3% to 82.7%]) and circulating Ang 1–7/Ang II ratios (+24.3% [95% CI: 0.4% to 59.6%]) respectively. Conclusions We extensively profiled plasma angiotensin peptides in HF patients and identified elevated ACE2 signature, reflected through the Ang 1–7/Ang II ratio, as an independent and incremental predictor of beneficial outcomes, higher survival rate, and decreased hospitalization duration. These findings provide important clinical evidence supporting strategies aiming to promote the beneficial ACE2/Ang 1–7/Mas receptor axis concurrent with RAS blockade therapies inhibiting the detrimental ACE/Ang II/AT1 receptor axis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Alberta Innovates, Canadian Institute of Health Research

Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects.

Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (P<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; P=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; P=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (P=0.02) and all other neurohormones were similar (P<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (P=0.20) or renal dysfunction (P>0.11 for all biomarkers), whereas both serum magnesium (P<0.001) and uric acid levels (P=0.008) improved. Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.

A055 Sex Differences in Ventricular Remodeling and Long-Term Heart Failure Outcomes Following Acute Coronary Syndrome

Compared with men, women are at increased risk of heart failure hospitalisation following acute coronary syndrome (ACS). We investigated whether this increased hazard was associated with differing left ventricular (LV) remodelling patterns over the first 12 months after ACS. In a prospective multi-centre observational cohort study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months. Heart failure events were captured over a median 4.8 (IQR 3.4-6.5) years and relative risk compared between women and men using a multivariable Cox model adjusted for baseline demographics (age and systolic blood pressure) and echocardiographic variables (LV end-diastolic and end-systolic volumes, LV ejection fraction, septal wall thickness, and E/e') captured at 1 and 12 months. The 609 (28.5%) women were older, had higher blood pressure, demonstrated smaller increases in cardiac biomarkers, and were less likely to undergo revascularisation during the index admission (41.9% versus 62.0%; p<0.001 for all). After indexing, women had smaller LV end-diastolic and end-systolic volumes, greater LV ejection fractions, and greater septal wall thickness and diastolic filling pressure estimates (E/e' 14 versus 11; p<0.001 for all). Diastolic volumes further diverged at 12 months (p=0.05) and septal wall thickness increased compared with men (p=0.016). In unadjusted and adjusted analyses women were at increased risk of heart failure hospitalisation (unadjusted HR 1.5, 95%CI 1.2-1.9, adjusted HR 1.6, 95%CI 1.1-2.4). Women experience a more concentric remodeling pattern following ACS. Women remain at increased risk of long-term heart failure hospitalisation after accounting for clinical and echocardiographic characteristics.Tabled 1≤65 years (n=963)>65 years (n=1177)pSex, men755 (78.4)776 (65.9)<0.001Systolic BP, mmHg124.22 (20.08)132.69 (22.42)<0.001LV end diastolic volume, indexed to BSA65.86 (19.27)65.87 (22.20)0.997% change from 1 to 12 months1.81 (26.47)3.59 (24.55)0.220LV end systolic volume, indexed to BSA28.64 (15.57)30.62 (19.23)0.029% change from 1 to 12 months2.60 (35.36)6.70 (41.09)0.064 Open table in a new tab

A054 Age-Related Differences in Ventricular Remodeling and Long-Term Heart Failure Outcomes Following Acute Coronary Syndrome

Older patients are at increased risk of heart failure following acute coronary syndrome (ACS). We investigated whether this hazard related to differing patterns in left ventricular (LV) remodeling. In a prospective multi-centre observational study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months following the index event with long-term heart failure hospitalisations captured for a median 4.8 (IQR 3.4-6.5) years. Individuals ≤65 years and those >65 years were compared using multivariable Cox models adjusted for baseline clinical (sex, blood pressure, revascularisation) and echocardiographic (LV end-diastolic/end-systolic volumes, LV ejection fraction, septal wall thickness, and E/e') variables recorded at 1 and 12 months. The 1177 (55%) participants who were >65 years were more likely to be women, had higher blood pressure, demonstrated smaller increases in cardiac biomarkers and were less likely to undergo coronary revascularisation (p<0.001 for all). At the 1-month visit, after indexing, older patients had similar LV end-diastolic but larger end-systolic volumes (p=0.029), lower LV ejection fractions, and greater LV mass and diastolic filling pressure estimates (E/e' 14 versus 10; p<0.001 for all). Systolic volumes appeared to further diverge at 12 months (p=0.064) however LV mass did not change in either group. In both unadjusted and adjusted analyses older patients were at increased risk of future heart failure hospitalisation (unadjusted HR 4.1, 95%CI 3.2-5.3; adjusted HR 2.4, 95%CI 1.5-3.9). Older patients experience more eccentric remodeling following ACS although remain at increased risk of heart failure hospitalisation after accounting for clinical and echocardiographic characteristics.Tabled 1≤65 years (n=963)>65 years (n=1177)p-valueLV end systolic volume, indexed to BSA28.64 (15.57)30.62 (19.23)0.029% change from 1 to 12 months2.60 (35.36)6.70 (41.09)0.064 Open table in a new tab

Nutrition intervention in heart failure: should consumption of the DASH eating pattern be recommended to improve outcomes?

Heart failure (HF) is a chronic, systemic disorder that presents a serious and growing public health problem due to its high prevalence, mortality, and cost of care. Due to the aging of the population and medical advances that prolong the life of HF patients, more effective, widespread strategies for improved HF management in this rapidly growing patient population are needed. While the prevalence of malnutrition in HF patients has been well characterized, evidence is limited regarding the effects of specific macro- and micronutrient deficiencies on HF outcomes and their interaction with other aspects of HF management, including pharmacotherapy. There is a mounting appreciation for the effects of nutritional intervention on pathophysiology, treatment, and outcomes in patients with HF. Heart-healthy dietary patterns, such as the Dietary Approaches to Stop Hypertension (DASH), carry importance for the prevention and treatment of hypertension. While preliminary evidence looks promising regarding effects of DASH eating pattern consumption on ventricular function and 30-day hospitalizations in HF patients, more research is needed to confirm its effects on short-term and long-term HF outcomes while better understand underlying mechanisms in the context of HF pharmacotherapy.

Bariatric Surgery in Patients with Systolic and Diastolic Heart Failure: Insights from the Nationwide Inpatient Sample

Purpose Obesity is an established risk factor for the development of heart failure (HF). Weight loss after bariatric surgery may have a positive impact in long-term HF outcomes; however, there is scarcity of data exploring the safety of bariatric surgery in this population. Methods Using the 2010-2015 Nationwide Inpatient Sample database, we identified the overall demographic characteristics and incidence of in-hospital complications in HF patients after bariatric procedures. Multivariate logistic regression was used to determine the relationship between HF and in-hospital outcomes. Results A total of 963,603 patients underwent bariatric procedures. Of these, 3,427 (0.36%) had systolic HF (sHF) and 6,327 (0.66%) had diastolic HF (dHF). Patients with HF were older and had a higher burden of comorbidities as appraised by Charlson Comorbidity Index (Table 1). HF patients had greater length of stay; this was consistent across sHF (4 vs 18 days; p Conclusion HF patients who underwent bariatric surgery in this national cohort had an increased risk of in-hospital complications when compared to patients without HF. Further studies are needed to better select candidates and balance the risk of short-term complications against potential long-term benefits.

HRelaxin-2 fusion protein treatment prevents isoproterenol-induced hypertrophy and fibrosis

Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, and heart failure. Anti-fibrotic therapy is promising for prevention and treatment of hypertrophic cardiomyopathy as the disease is associated with interstitial fibrosis. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone, and hRelaxin-2 fusion protein (hRLX-2). Comparatively, hRLX-2 has an extended half-life, potential superior efficacy, and convenient dosing, which suggests an improved safety profile. The purpose of this study was to test whether hRLX-2 is protective in cardiac hypertrophy and fibrosis. Isoproterenol was used to induce cardiac hypertrophy model in C57BL6J mice. Vehicle or isoproterenol (15 mg/kg/day) was delivered via Alzet minipumps for 14 days, and hRLX-2 (30 mg/kg) was given twice by subcutaneous injection at day 0 and 7. For comparison, a group with serelaxin (500 mg/kg/day, un-modified recombinant human relaxin-2) or enalapril (2.5 mg/kg/day, an ACE inhibitor) was co-infused with isoproterenol. Isoproterenol increased cardiac hypertrophy (as measured by heart weight/body weight, heart weight/tibial length, and echocardiography) and fibrosis (collagen content and histological assessment) compared to vehicle. H-RLX-2, enalapril or serelaxin treatments attenuated the isoproterenol induced cardiac hypertrophy and fibrosis. Isoproterenol-induced hypertrophy significantly increased TGFβ1/Smad-induced fibrotic signaling, which was attenuated by hRLXn-2. Consistent with a previous study using seralaxin, we found that hRLX-2 significantly increased AKT/eNOS signaling. In addition, hRLX-2 treatment increased protein S-nitrosylation, which has been shown in other cardioprotective models. These findings support a potential role for hRLX-2 in the treatment of hypertrophic myocardiopathy.

New-Onset Heart Failure and Mortality in Hospital Survivors of Sepsis-Related Left Ventricular Dysfunction.

The association between new-onset left ventricular (LV) dysfunction during sepsis with long-term heart failure outcomes is lesser understood. Retrospective cohort study of all adult patients with severe sepsis and septic shock between 2007 and 2014 who underwent echocardiography within 72 h of admission to the intensive care unit. Patients with prior heart failure, LV dysfunction, and structural heart disease were excluded. LV systolic dysfunction was defined as LV ejection fraction <50% and LV diastolic dysfunction as ≥grade II. Primary composite outcome included new hospitalization for acute decompensated heart failure and all-cause mortality at 2-year follow-up. Secondary outcomes included persistent LV dysfunction, and hospital mortality and length of stay. During this 8-year period, 434 patients with 206 (48%) patients having LV dysfunction were included. The two groups had similar baseline characteristics, but those with LV dysfunction had worse function as demonstrated by worse LV ejection fraction, cardiac index, and LV diastolic dysfunction. In the 331 hospital survivors, new-onset acute decompensated heart failure hospitalization did not differ between the two cohorts (15% vs. 11%). The primary composite outcome was comparable at 2-year follow-up between the groups with and without LV dysfunction (P = 0.24). Persistent LV dysfunction was noted in 28% hospital survivors on follow-up echocardiography. Other secondary outcomes were similar between the two groups. In patients with severe sepsis and septic shock, the presence of new-onset LV dysfunction did not increase the risk of long-term adverse heart failure outcomes.

Pulmonary Vascular Resistance During Exercise Predicts Long-Term Outcomes in Heart Failure With Preserved Ejection Fraction

BackgroundIn heart failure with preserved ejection fraction (HFpEF), the prognostic value of pulmonary vascular dysfunction (PV-dysfunction), identified by elevated pulmonary vascular resistance (PVR) at peak exercise, is not completely understood. We evaluated the long-term prognostic implications of PV-dysfunction in HFpEF during exercise in consecutive patients undergoing invasive cardiopulmonary exercise testing for unexplained dyspnea. MethodsPatients with HFpEF were classified into 2 main groups: resting HFpEF (n = 104, 62% female, age 61 years) with a pulmonary arterial wedge pressure (PAWP) >15 mmHg at rest; and exercise HFpEF (eHFpEF; n = 81) with a PAWP <15 mmHg at rest, but >20 mmHg during exercise. The eHFpEF group was further subdivided into eHFpEF + PV-dysfunction (peak PVR ≥80 dynes/s/cm−5; n = 55, 60% female, age 64) group and eHFpEF – PV-dysfunction (peak PVR <80 dynes/s/cm−5; n = 26, 42% female, age 54 years) group. Outcomes were analyzed for the first 9 years of follow-up and included any cause mortality and heart failure (HF)-related hospitalizations. The mean follow-up time was 6.7 ± 2.6 years (0.5–9.0). ResultsMortality rate did not differ among the groups. However, survival free of HF-related hospitalization was lower for the eHFpEF + PV-dysfunction group compared with eHFpEF – PV-dysfunction (P = .01). These findings were similar between eHFpEF + PV-dysfunction and the resting HFpEF group (P = .774). By Cox analysis, peak PVR ≥80 dynes/s/cm−5 was a predictor of HF-related hospitalization for eHFpEF (hazard ratio 5.73, 95% confidence interval 1.05–31.22, P = .01). In conclusion, the present study provides insight into the impact of PV-dysfunction on outcomes of patients with exercise-induced HFpEF. An elevated peak PVR is associated with a high risk of HF-related hospitalization.