Advanced Heart Failure With Reduced Ejection Fraction Research Articles

Parâmetros de Strain Diastólico Estão Associados à Mortalidade em Curto Prazo e à Reinternação em Pacientes com Insuficiência Cardíaca Avançada

Abstract Background Heart failure (HF) is a leading cause of hospitalization and mortality worldwide and places a great economic burden on healthcare systems. Identification of prognostic factors in HF patients is of great importance to establish optimal management strategies and to avoid unnecessary invasive and costly procedures in end-stage patients. Objectives In the current study, we aimed to investigate the association between diastolic strain parameters including E/e’ SR, and short-term outcomes in advanced HF patients. Methods The population study included 116 advanced HF with reduced ejection fraction (HFrEF) patients. Clinical, laboratory, and echocardiographic evaluations of the patients were performed within the first 24 hours of hospital admission. Patients were followed for one month and any re-hospitalization due to worsening of HF symptoms and any mortality was recorded. The level of significance adopted in the statistical analysis was 5%. Results E/e’ SR was significantly higher in the patient group compared to the control group (p=0.001). During one-month follow-up, 13.8% of patients died and 37.1% of patients were rehospitalized. Serum NT-ProBNP (p=0.034) and E/e’ SR (p=0.033) were found to be independent predictors of mortality and ACEİ use (p=0.027) and apical 3C strain (p=0.011) were found to be independent predictors of rehospitalization in the patient group. Conclusion Findings of the current prospective study demonstrate that E/e’ SR measured by speckle tracking echocardiography is an independent and sensitive predictor of short-term mortality in advanced HFrEF patients and may have a role in the identification of end-stage HFrEF patients.

Diastolic Strain Parameters are Associated with Short Term Mortality and Rehospitalization in Patients with Advanced Heart Failure.

Heart failure (HF) is a leading cause of hospitalization and mortality worldwide and places a great economic burden on healthcare systems. Identification of prognostic factors in HF patients is of great importance to establish optimal management strategies and to avoid unnecessary invasive and costly procedures in end-stage patients. In the current study, we aimed to investigate the association between diastolic strain parameters including E/e' SR, and short-term outcomes in advanced HF patients. The population study included 116 advanced HF with reduced ejection fraction (HFrEF) patients. Clinical, laboratory, and echocardiographic evaluations of the patients were performed within the first 24 hours of hospital admission. Patients were followed for one month and any re-hospitalization due to worsening of HF symptoms and any mortality was recorded. The level of significance adopted in the statistical analysis was 5%. E/e' SR was significantly higher in the patient group compared to the control group (p=0.001). During one-month follow-up, 13.8% of patients died and 37.1% of patients were rehospitalized. Serum NT-ProBNP (p=0.034) and E/e' SR (p=0.033) were found to be independent predictors of mortality and ACEİ use (p=0.027) and apical 3C strain (p=0.011) were found to be independent predictors of rehospitalization in the patient group. Findings of the current prospective study demonstrate that E/e' SR measured by speckle tracking echocardiography is an independent and sensitive predictor of short-term mortality in advanced HFrEF patients and may have a role in the identification of end-stage HFrEF patients.

Right ventricular-pulmonary arterial uncoupling and ventricular-secondary mitral regurgitation: Relationship with outcomes in advanced heart failure

BackgroundSecondary mitral regurgitation (MR) is common in heart failure with reduced ejection fraction (HFrEF) and associated with poor outcomes. However, there is little evidence regarding secondary MR in advanced HFrEF. Poor outcomes for MR intervention suggest a need for further risk stratification. ObjectivesWe hypothesized adverse prognosis in right ventricles (RV) less able to compensate for increased pulmonary pressures of post-capillary cause in the context of secondary MR. MethodsPatients were assessed with echocardiography, right heart catheterisation (RHC) and cardiopulmonary exercise testing. Ventricular-secondary MR was identified by echocardiography and categorised mild, moderate, or severe according to guidelines. RV ability to compensate for pulmonary pressure rise was assessed by RV-pulmonary artery (PA) coupling, calculated as ratio of tricuspid annular plane systolic excursion (TAPSE) and systolic pulmonary artery pressure (SPAP) (echocardiography for TAPSE and RHC for SPAP). Primary endpoint was a composite of all-cause mortality, urgent heart transplantation or mechanical circulatory support. Results456 patients with ventricular-secondary MR were followed up for a median of 2.39 years, with 237 reaching a primary endpoint. Severe MR conferred a worse prognosis than mild or moderate (HR 2.6, p<0.001). Right atrial pressure was predictive of survival. RV-PA uncoupling, defined as TAPSE/SPAP below median value of 0.37, was associated with reduced survival across all severities of mitral regurgitation (p<0.001). ConclusionsVentricular-secondary MR is common and severity correlates with adverse prognosis in advanced heart failure. RV-PA uncoupling can improve risk stratification in all grades of MR severity, particularly with PA pressure determined invasively.

HFrEF phenotyping in real life

Abstract Background In May 2021 an HFA position paper[1] by Rosano GMC et al. classified patients with heart failure with reduced ejection fraction (HFrEF) into 11 phenotypes based on blood pressure, heart rate, renal function, potassium level and rhythm and assigned them to different prescription attitudes. Aim We aim to investigate the distribution of phenotype frequency in our cohort and their respective outcomes. Methods From 2016 to 2022 we enrolled 900 advanced HFrEF patients with severely reduced ejection fraction (LVEF &amp;lt;35%) in a prospective registry from our tertiary care heart failure unit. Patients were grouped according to the suggested phenotypes. Distribution and outcome for the different groups was analyzed. Results Characteristics of the different phenotypes, the distribution and outcome are shown in Figure 1. 65.8% of patients belong to 5 categories [3, 4, 5, 7b and 9]. Baseline characteristics of these 5 profiles are shown in Table 1. With the exception of Profile 3, which is characterized by a low resting hear rate, these major profiles are all eligible to receive all 4 drugs with class I recommendation at maximal dosages (RASi, BB, MRA, SGLT2i). The 6 remaining categories, all with GDMT limiting features, comprise solely another 3.8% of patients [1.8%, 1.2%, 0.3%, 0.3%, 0.2%, 0%, for the categories 7c, 7a, 1, 2, 6, 8 respectively]. With 30.2% a significant proportion of patients could not be assigned to one profile exclusively mostly because they showed a combination of profile attributes. Thus, of all classifiable HFrEF patients, with 83.4% the majority has no GDMT limiting features and should receive full HFrEF therapy. All-cause mortality did not differ between patient phenotypes [4,5,7b and 9] and the others (p = 0.193), while uncategorizable patients had significantly worse survival (p&amp;lt;0.0001) (Figure 1c). Conclusion The study provides insight into heart failure phenotyping in a real-world setting. Most HFrEF patients are eligible for the 4 class I drugs of HFrEF medication, and only a minority may not be able to receive them. However, nearly one-third of all patients could not be categorized, including those with the poorest survival. Given these findings, the added value of the classification of patients according to this pattern seems limited in routine practice, possibly resulting from the complexity of the clinical picture of HFrEF.Figure 1 BL characteristics

Abstract 17090: Prognostic Value of Creatinine versus Cystatin C-Based Estimation of Glomerular Filtration Rate for Mortality in Heart Failure

Introduction: Serum creatinine and cystatin C are filtration markers used to calculate estimated glomerular filtration rate (eGFR). Lower eGFR using both is associated with increased mortality in heart failure with reduced ejection fraction (HFrEF). Cystatin C may be more accurate in advanced HFrEF with sarcopenia. Prognostic ability of each (eGFRcr or eGFRcys) or their weighted average (eGFRcr-cys) has not been compared. Hypothesis: eGFRcr-cys is more predictive of mortality in HFrEF than eGFRcr or eGFRcys. Methods: We analyzed data from 310 participants from Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with baseline serum creatinine and cystatin C. Primary outcome was all-cause mortality. Cox models were adjusted for age, sex, race, diabetes mellitus, and NYHA class. Results: Median eGFR by cr, cys and cr-cys were 60, 58 and 60 ml/min/1.73m 2 . During 2-year follow-up, 45 participants died. Within each patient, the difference of eGFRcr and eGFRcys varied from -49 to 50 ml/min/1.73m 2 . Among all estimates, those with baseline eGFR &lt;60 ml/min/1.73m 2 had worse survival (Figure). Lower baseline eGFRcr [HR 0.97, 95% CI (0.96-0.99), P =0.008, C= 0.67], eGFRcys [HR 0.98 (0.97-0.99), P= 0.006, C= 0.68], and eGFRcr-cys [HR 0.98 (0.96-0.99), P= 0.004, C= 0.68] were associated with higher mortality. C-statistic comparison did not show a significant difference for predictive ability: eGFRcr vs. eGFRcys, P=0.7; eGFRcr vs. eGFRcr-cys, P=0.9; eGFRcys vs. eGFRcr-cys, P=0.3). Conclusions: Using all three estimates, lower eGFR was associated with higher mortality, although all had relatively poor predictive performance. eGFRcys was expected to be similar to or lower than eGFRcr due to decreased muscle mass, yet at the individual level there was wide variability between estimates which could in part explain their poor predictive abilities. There is need for more specific kidney filtration markers for prediction of mortality in HFrEF.

Is there any difference in the therapeutic effects of Levosimendan on advanced HFrEF patients with sinus rhythm or atrial fibrillation?

Patients with advanced heart failure have a high incidence of atrial fibrillation (AF) and develop into heart failure with reduced ejection fraction (HFrEF), and require higher doses of inotropes. However, it is uncertain about the differences in the effects of levosimendan in HFrEF patients with sinus rhythm or AF. A total of 63 advanced HFrEF subjects (ejection fraction < 40%) were divided into sinus rhythm (SR, n = 34) and atrial fibrillation (AF, n = 29) cohorts. All patients received six cycles of intermittent repeated levosimendan infusion. After 3 months of treatment, B-type natriuretic peptide (BNP), estimated glomerular filtration rate, resting heart rate (rHR), creatinine, left ventricle ejection fraction (LVEF), left ventricular end diastolic diameter and blood pressure body weight, NYHA classification were measured. After completing the course of treatment, LVEF, BNP, and rHR were significantly decreased (p < 0.0.5), and no significant differences between the two groups were observed (p > 0.05). The NYHA classification improved in the SR group but not in the AF group. There was no significant difference between patients with different rHRs (≤70 bpm vs. >70 bpm) in the SR group (p > 0.05) or in the AF group (rHR ≤ 90 bpm vs. rHR >90 bpm) (p > 0.05). This study showed no difference in the therapeutic effect of intermittent repeated levosimendan infusion on advanced HFrEF with different heart rhythms (SR or AF); Advanced HFrEF patients receive levosimendan treatment without taking the inference of heart rhythm.

Omecamtiv mecarbil augments cardiomyocyte contractile activity both at resting and systolic Ca2+ levels.

Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca2+ sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca2+ -sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included. Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura-2AM, a Ca2+ -sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca2+ concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1Hz in the presence of different OM, EMD, or Levo concentrations. SL was reduced by about 23% or 9% in the presence of 1μM OM or 1μM EMD in the absence of electrical stimulation, whereas 1μM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1μM EMD or 1μM Levo to about 152%, but only to about 128% in the presence of 0.03μM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One-micromole EMD or 1μM Levo had no effects on contraction durations. One-micromole Levo, but not 1μM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca2+ transient amplitudes were unaffected by all treatments. Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca2+ -sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca2+ -sensitizing effect.

Reflecting on the advancements of HFrEF therapies over the last two decades and predicting what is yet to come.

What was once considered a topic best avoided, managing heart failure with reduced ejection fraction (HFrEF) has become the focus of many drug and device therapies. While the four pillars of guideline-directed medical therapies have successfully reduced heart failure hospitalizations, and some have even impacted cardiovascular mortality in randomized controlled trials (RCTs), patient-reported outcomes have emerged as important endpoints that merit greater emphasis in future studies. The prospect of an oral inotrope seems more probable now as targets for drug therapies have moved from neurohormonal modulation to intracellular mechanisms and direct cardiac myosin stimulation. While we have come a long way in safely providing durable mechanical circulatory support to patients with advanced HFrEF, several percutaneous device therapies have emerged, and many are under investigation. Biomarkers have shown promise in not only improving our ability to diagnose incident heart failure but also our potential to implicate specific pathophysiological pathways. The once-forgotten concept of discordance between pressure and volume, the forgotten splanchnic venous and lymphatic compartments, have all emerged as promising targets for diagnosing and treating heart failure in the not-so-distant future. The increase in heart failure-related cardiogenic shock (CS) has revived interest in defining optimal perfusion targets and designing RCTs in CS. Rapid developments in remote monitoring, telemedicine, and artificial intelligence promise to change the face of heart failure care. In this state-of-the-art review, we reminisce about the past, highlight the present, and predict what might be the future of HFrEF therapies.

IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction: Findings From DAPA-HF

BackgroundInsulin-like growth factor–binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. ObjectivesThe authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. MethodsThe primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. ResultsA total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). ConclusionsHigher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

The effect of kidney dysfunction on introducing guideline-derived medical therapy and on mortality among hospitalized patients with heart failure with reduced ejection fraction

Abstract Introduction Chronic kidney disease (CKD) is one of the main limiting factors of introducing and uptitrating guideline-derived medical therapy (GDMT) among patients with heart failure with reduced ejection fraction (HFrEF). Only few studies evaluated the success of implementation of pharmacotherapy in HFrEF and its effect on prognosis across the whole spectrum of CKD stages. Aim To analyze the implementation differences of mortality reducing triple therapy (ACEi/ARB/ARNI + BB + MRA) by severity of CKD among hospitalized HFrEF patients. Furthermore, we evaluated the association between mortality and CKD stages. Patients and methods 257 consecutive, hospitalized HFrEF patients' data were analyzed retrospectively, who had been hospitalized at the Heart Failure Unit of a tertiary cardiological centre in 2019–2021 (male: 74%, age: 65 [56–73] years, ischemic: 45%, diabetes: 40%, hypertension 58%, atrial fibrillation 46%, LVEF: 25 [20–30] %, NT-proBNP at admission: 6086 [2757–11994] pg/ml). Median eGFR was 58 [39–74] ml/min/1.73 m2, 53% of patients had eGFR &amp;lt;60 ml/min/1.73 m2 (CKD stage: G1 – eGFR &amp;gt;90 ml/min/1.73 m2: 15%, G2 – eGFR = 60–90 ml/min/1.73 m2: 32%, G3A – eGFR = 45–59 ml/min/1.73 m2: 20%, G3B – eGFR = 30–44 ml/min/1.73 m2: 21%, G4 – eGFR = 15–29 ml/min/1.73 m2: 9%, G5 – eGFR &amp;lt;15 ml/min/1.73 m2: 3%). 1% of patients was on dialysis. The success of implementing triple-therapy depending on CKD stages was investigated with Chi-square test, while mortality differences were analyzed with Kaplan-Meier method. Results The severity of CKD led to significantly (p&amp;lt;0.0001) lower implementation rate of triple-therapy (CKD stage G1–G2–G3A–G3B–G4–G5: 92 vs. 87 vs. 81 vs. 74 vs. 29 vs. 43%). However, only the ratio of RASi use showed significant difference (p&amp;lt;0.0001) among CKD subgroups (stage G1–G2–G3A–G3B–G4–G5: 100 vs. 100 vs. 92 vs. 87 vs. 42 vs. 43%), while BB (CKD stage G1–G2–G3A–G3B–G4–G5: 92 vs. 88 vs. 88 vs. 81 vs. 71 vs. 71%; p=0.162) and MRA (CKD stage G1–G2–G3A–G3B–G4–G5: 97 vs. 98 vs. 96 vs. 93 vs. 83 vs. 100%; p=0.0899) implementation was independent of renal function. All-cause 6-month mortality was 14% in the whole population. 6-months mortality rates proved to be higher (p=0.0083) in patients with more severe CKD (stage G1–G2–G3A–G3B–G4–G5: 8 vs. 11 vs. 8 vs. 20 vs. 35 vs. 29%). Conclusions Patients with advanced HFrEF and concomitant CKD are not equally treated with GDMT, even though kidney dysfunction is not an absolute contraindication of cornerstone HFrEF therapies. HFrEF patients with more severe CKD have poorer prognosis, thus implementation of mortality- and morbidity reducing drug therapy according to the guidelines is essential. Funding Acknowledgement Type of funding sources: None.

Comparative prognostic value of parameters of right ventricular pulsatile afterload in patients with advanced heart failure awaiting heart transplantation

Abstract Background Right ventricular (RV) function demonstrated a strong impact on survival of patients with advanced heart failure with reduced ejection fraction (HFrEF). In particular, increased RV pulsatile afterload (RVPA) was associated with poor prognosis. Several right heart catheterization-derived parameters have been proposed to characterize RVPA, including pulmonary artery compliance (PAC), elastance (PAE) and pulsatile index (PAPi). However, among these indices, the best prognostic indicator is undetermined. Purpose To assess the prognostic relevance of RVPA parameters in patients with advanced HFrEF evaluated for heart transplantation. Methods 149 patients with end-stage HFrEF underwent right heart catheterization during the evaluation for heart transplantation. All patients were clinically followed up until death or any censoring events including heart transplantation, left ventricular assist device (LVAD) and hospitalization for acute heart failure. Cox regression and ROC-curve analysis were used to test the prognostic value of RVPA determinants. Multivariate regression models with C-statistics were used to test the independent predictive value of RVPA indices. Results The mean age of the study population was 56.6±10.1 years and 85.2% were male. The most frequent aetiology of HFrEF was ischemic cardiomyopathy (52.3%). Mean LV ejection fraction was 25.7±10.2%. During a mean follow up time of 17±15 months, 29 (19.5%) patients met the primary endpoint: 9 (6%) patients died, 4 (2.68%) patients underwent an urgent heart transplantation, 11 (7.3%) patients underwent urgent LVAD implantation (as bridge to transplantation therapy) and 5 (3.3%) were hospitalized for HF. Patients who met the primary endpoint were significantly older patients (61.2±7.8 vs 55.4±10.2, p=0.006) and with worse hemodynamic profile than event-free survivors (PAC [1.8±0.8 vs. 2.7±2.0, p=0.01], mPAP [33.5±11.3 vs. 29.3±11.0, p=0.05], PVR [3.0±1.6 vs. 2.6±2.0, p=0.09] and PAE [1.12±0.5 vs. 0.98±0.6, p=0.04]). Among the RVPA parameters PAC&amp;lt;1.9 mL/mmHg (HR 4.0, CI 1.3–6.0, p=0.007) and PAE&amp;gt;0.9 mmHg/mL (HR 2.5, 95% CI 1.1–5.2, p=0.02) were associated with the primary endpoint. On the contrary, PAPi was not significantly associated with the outcome. PAC demonstrated a superior predictive value for the composite adverse outcome compared with pulmonary vascular resistances (PVR) (AUC comparison p=0.019) and PAPi (p=0.03) but similar compared with PAE (p=0.19) and mPAP (p=0.51). In multivariable regression models, PAC, but not PAE showed incremental prognostic value compared with cardiac index (p=0.02). Conclusions Hemodynamic indices of RVPA are associated with worse survival in patients with end-stage heart failure. In particular, PAC and PAE demonstrated superior prognostic value compared with PAPi and steady-state PVR. Moreover, PAC showed incremental prognostic value compared with cardiac index in patients awaiting heart transplantation. Funding Acknowledgement Type of funding sources: None.

Evaluation of RV-arterial coupling in advanced heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The ratio of echocardiography-derived tricuspid annular plane systolic excursion (TAPSE) and pulmonary arterial systolic pressure (PASP) - TAPSE/PASP ratio - is a noninvasive measure of RV-arterial coupling. TAPSE/PASP ratio is a potent independent predictor of prognosis in heart failure and pulmonary arterial hypertension, with a prognostic cutoff value of 0.36 mm/mmHg. Objective To assess the prognostic impact of TAPSE/PASP ratio in a population of advanced HF patients. Methods Prospective evaluation of adult patients with advanced HFrEF referred to our Institution for evaluation with HF team and possible indication for urgent heart transplantation (HT) or MCS. Patients were followed up for 2 years for the primary endpoint of cardiac death and HT. Echocardiographically determined TAPSE/PASP ratio was used to assess RV-arterial coupling and a survival analysis was performed to evaluate the prognostic impact of the suggested cutoff of 0.36 mm/mmHg. Results A total of 450 Heart Failure with Reduced Ejection Fraction (HFrEF) patients with a mean age of 56 ± 12 years, of which 80% are male, and with a mean LVEF of 29 ± 4%, mean TAPSE of 19 ± 3 mm and PASP of 38 ± 11mmHg. The mean TAPSE/PASP was 0.80 ± 0.28. Fifty-four patients (12%) met the primary endpoint. Patients with RV-arterial uncoupling (TAPSE/PASP &amp;lt; 0.36 mm/mmHg) were more likely to have a non-ischaemic etiology for HF (66.7% vs 40%, p = 0.047), had a lower prevalence of diabetes (53.3% vs 77.9%, p = 0.041), a higher prevalence of moderate-to-severe mitral regurgitation (33.3% vs 13.0%, p = 0.035), a lower LVEF (26.2 ± 6.1 vs 29.9 ± 5.9, p = 0.038), a higher prevalence of RV dysfunction (73.3% vs 26.7%, p &amp;lt; 0.001) and worse cardiopulmonary fitness (pVO2: 12.7 ± 5.1 vs 15.8 ± 6.0 ml/kg/min, p = 0.047; VE/VCO2 slope: 49.5 ± 17.2 vs 37.6 ± 9.7, p &amp;lt; 0.001; cardiorespiratory optimal point: 36.9 ± 11.3 vs 29.0 ± 6.4, p &amp;lt; 0.001). More patients in the group of TAPSE/PASP &amp;lt; 0.36 mm/mmHg met the primary endpoint (33.3% vs 9.6%, p = 0.034) and more patients underwent urgent HT (13.3% vs 1.4%, p = 0.44). RV-arterial coupling was associated with a lower survival free of events during follow-up (log-rank p = 0.010). Conclusion RV-arterial coupling predicts a worse prognosis in advanced HF patients, with those below a cutoff of 0.36 mm/mmHg having lower survival. This variable may improve risk stratification in this setting. Abstract Figure.

Prognostic impact of right ventricular function in advanced heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Introduction In patients with heart failure with reduced ejection fraction (HFrEF), the presence of coexistent right ventricular (RV) systolic dysfunction is associated with a worse functional capacity and outcome. However, the measurement of RV function is often overshadowed by its left counterpart. Purpose To assess the prognostic impact of RV dysfunction in a population of advanced HF patients. Methods Prospective evaluation of adult patients with advanced HFrEF referred to our Institution for evaluation with HF team for possible indication for urgent heart transplantation (HT) or MCS. Patients were followed up for 1 year for the primary endpoint of cardiac death and HT. RV systolic dysfunction was defined by a tricuspid annular plane systolic excursion (TAPSE) &amp;lt; 17 mm and/ or fractional area change (FAC) &amp;lt; 35%. A survival analysis was performed to evaluate the prognostic impact of RV dysfunction and survival curves were compared using the log-rank test. Results A total of 450 HFrEF patients (mean age of 56 ± 12 years, 80% male, mean LVEF of 29 ± 4%, mean TAPSE of 19 ± 3 mm and RV FAC of 37 ± 6%), of which 30.4% had RV dysfunction. Thirty patients (6.7%) met the primary endpoint. Patients with RV dysfunction had a higher NT-proBNP value (3278.9 ± 296.7 pg/mL, p = 0.005) and a lower LVEF (26.7 ± 6.4 vs 31.4 ± 5.1, p &amp;lt; 0.001), as well as a worse cardiopulmonary fitness (CPET duration: 7.2 ± 3.8 vs 8.6 ± 4.1, p = 0.019; pVO2: 13.6 ± 4.9 vs 16.2 ± 6.1 ml/kg/min, p = 0.006; VE/VCO2 slope: 41.8 ± 11.9 vs 37.0 ± 10.6, p = 0.015; cardiorespiratory optimal point: 33.0 ± 8.9 vs 28.4 ± 6.2, p &amp;lt; 0.001). RV dysfunction was associated with a lower survival free of events during the first follow-up year (log-rank p = 0.046). Conclusion RV is associated with a poor survival in advanced HF patients and it may improve risk stratification in this population. Abstract Figure.

Contemporary Drug Treatment of Advanced Heart Failure with Reduced Ejection Fraction.

The introduction of multiple new pharmacological agents over the past three decades in the field of heart failure with reduced ejection fraction (HFrEF) has led to reduced rates of mortality and hospitalizations, and consequently the prevalence of HFrEF has increased, and up to 10% of patients progress to more advanced stages, characterized by high rates of mortality, hospitalizations, and poor quality of life. Advanced HFrEF patients often show persistent or progressive signs of severe HF symptoms corresponding to New York Heart Association class III or IV despite being on optimal medical, surgical, and device therapies. However, a subpopulation of patients with advanced HF, those with the most advanced stages of disease, were often insufficiently represented in the major trials demonstrating efficacy and tolerability of the drugs used in HFrEF due to exclusion criteria such as low BP and kidney dysfunction. Consequently, the results of many landmark trials cannot necessarily be transferred to patients with the most advanced stages of HFrEF. Thus, the efficacy and tolerability of guideline-directed medical therapies in patients with the most advanced stages of HFrEF often remain unsettled, and this knowledge is of crucial importance in the planning and timing of consideration for referral for advanced therapies. This review discusses the evidence regarding the use of contemporary drugs in the advanced HFrEF population, covering components such as guideline HFrEF drugs, diuretics, inotropes, and the use of HFrEF drugs in LVAD recipients, and provides suggestions on how to manage guideline-directed therapy in this patient group.

393 Long-term prognostic value of haemodynamic determinants of right ventricular pulsatile afterload in patients with advanced heart failure

Abstract Aims Right ventricular (RV) dysfunction demonstrated a strong impact on survival of patients with advanced heart failure with reduced ejection fraction (HFrEF). Increased RV afterload is associated with poor prognosis in patients with HF. To examine the prognostic relevance of RV pulsatile afterload parameters, in particular pulmonary artery compliance (PAC), elastance (PAE), and pulsatile index (PAPi) in a large cohort of patients with advanced HFrEF evaluated for heart transplantation (HT). Methods and results 149 patients with HFrEF enlisted for HT were evaluated with right heart catheterization (RHT) and echocardiography and were followed until death or any censoring events including HT, left ventricular assist device (LVAD), and hospitalization for acute heart failure (HHF). Cox regression and ROC-curve analysis were used to test the prognostic value of RV pulsatile afterload determinants. During a mean observation time of 500 ± 424 days, the primary endpoint occurred in 29 (19.5%) patients. The mean age was 56.6 ± 10.1 years and 85.2% were male. The most frequent etiology of HF was ischaemic cardiomyopathy (52.3%). Mean LV ejection fraction was 25.7 ± 10.2%. Patients who met the primary endpoint were significantly older and with worse haemodynamic profile than event-free survivors. In particular, the primary endpoint occurred in patients with lower PAC (1.8 ± 0.8 vs. 2.7 ± 2.0, P = 0.01), higher mean pulmonary arterial pressure (mPAP) (33.5 ± 11.3 vs. 29.3 ± 11.0, P = 0.05), PVR (3.0 ± 1.6 vs. 2.6 ± 2.0, P = 0.09), and PEA (1.12 ± 0.5 vs. 0.98 ± 0.6, P = 0.04). A significant increased risk of adverse outcome was observed in patients with PAC &amp;lt;1.9 ml/mmHg (HR: 3, 95% CI: 1.3–6, P = 0.007), PEA &amp;gt; 0.9 mmHg/ml (HR: 2.5, 95% CI: 1.1–5.2, P = 0.02) and mPAP ≥25 mmHg (HR: 3.0, 95% CI: 1.0–7.5, P = 0.03). The predictive value of PAC was superior compared with PVR (AUC comparison, P = 0.019) and PAPi (P = 0.03). Conversely, PAC presented similar prognostic accuracy compared with mPAP (P = 0.51) and PEA (P = 0.19). Moreover, PAC demonstrated incremental prognostic value compared with the cardiac index (P = 0.02), whereas mPAP and PAE did not. Conclusions Impaired haemodynamic RV parameters are associated with worse survival in patients with advanced HFrEF. Pulsatile RV afterload indices should be considered in the evaluation of patients enlisted for HT. PAC demonstrated an independent prognostic value in this highly selected cohort of patients awaiting HT.

Abstract 13045: Metformin in Management of Diabetic Patients With Advanced Heart Failure (HFrEFf): A Propensity Score-Matched Analysis

Introduction: The role of metformin (MET) in the treatment of patients with advanced heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (DM) is not firmly established. Hypothesis: Meformin treatment will be associated with better outcome even in DM patients with advanced HFrEF. Methods: A total of 847 stable patients with advanced HFrEF (57.4± 11.3 years, 67.7% NYHA III/IV, LVEF 23.6± 5.8%) underwent clinical and laboratory evaluation and were prospectively followed for a median of 1126 (IQRs 410; 1781) days for occurrence of death, urgent heart transplantation or mechanical circulatory support implantation. A subgroup of 380 patients (44.9%) had DM, 87 of DM patients (22.9%) were treated with MET. Results: Compared with MET-free diabetic patients, MET-treated individuals had similar fasting glucose, but worse DM control (Hb1Ac 60 mmol/mol, IQRs 50-73 vs. 52 IQRs 48-62, p=0.002), higher insulin, glucagon, β-hydroxybutyrate levels and increased insulin resistance (all p&lt; 0.05), but better quality of life (MLHFQ-score: 36 vs. 48 points, p= 0.002). Compared to diabetics treated with any other glucose-lowering agent, MET-treated patients had better event-free survival (p=0.0005, Fig. 1), which remained significant (p= 0.035) even after adjustment for BNP, BMI and eGFR. Propensity score-matched analysis with 17 covariates yielded 81 pairs of patients and showed a significantly better survival for MET-treated subgroup (p= 0.01). Conclusions: MET treatment in patients with advanced HFrEF and DM is associated with better quality of life and improved outcome, by mechanisms beyond the improvement of blood glucose control. MET should stay among frontline drugs for treatment of HFrEF patients with DM. Supported by a grant no. NV19-02-00130 by Czech Health Research Council.

Digoxin in Patients With Advanced Heart Failure and Sinus Rhythm Submitted to Cardiac Resynchronization Therapy-Is There Any Benefit?

Digoxin (DG) use in patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm remains controversial. We aimed to assess the prognostic effect of DG in patients in sinus rhythm submitted to cardiac resynchronization therapy (CRT). Retrospective study including 297 consecutive patients in sinus rhythm, with advanced HFrEF submitted to CRT. Patients were divided into 2 groups: with DG and without DG (NDG). During a mean follow-up of 4.9 ± 3.4 years, we evaluated the effect of DG on the composite end point defined as cardiovascular hospitalization, progression to heart transplantation, and all-cause mortality. Previous to CRT, 104 patients (35%) chronically underwent DG and 193 patients (65%) underwent NDG treatment. The 2 groups did not differ significantly regarding HF functional class, HF etiology, QRS, and baseline left ventricular ejection fraction. The proportion of responders to CRT was similar in both groups (54% in DG vs. 56% in NDG; P = 0.78). During the long-term follow-up period, the primary end point occurred in a higher proportion in DG patients (67 vs. 48%; P = 0.002). After adjustment for potential confounders, DG use remained as an independent predictor of the composite end point of CV hospitalization, heart transplantation, and all-cause mortality [hazards ratio = 1.58; confidence interval, 95 (1.01-2.46); P = 0.045]. In conclusion, in patients in sinus rhythm with HFrEF submitted to CRT, DG use was associated with CV hospitalization, progression to heart transplant, and all-cause mortality.

10-year survival in patients undergoing cardiac resynchronization therapy

Abstract Background Advanced heart failure with reduced ejection fraction (HFrEF) is associated with poor prognosis. Cardiac resynchronization therapy (CRT) is an effective method of treatment for advanced HFrEF to reduce HF hospitalizations and mortality. Nonetheless, very long-term observation of HF patients undergoing CRT implantation is scarce. Aim To assess very long-term survival (≥10 years) and predictors of shorter survival (death within 10 years from CRT implantation). Methods We screened a large dataset of CRT population from a tertiary care university hospital comprising consecutive HF patients implanted with CRT from 2002 through 2019 to select those who were alive ≥10 years and those who died within 10 years since device implantation. We analyzed various patients' baseline, clinical and procedural characteristics and sought for predictors of mortality within 10 years from CRT implantation. Results Of 1059 CRT patients, 143 (13.5%) were alive ≥10 years since CRT implantation. On multivariable regression analysis the independent predictors for all-cause death up to 10 years from CRT implantation were as follows: age, HR 1.02, 95% CI 1.01–1.31; male sex, 1.27, 95% CI 1.01–1.60; primary prevention of sudden cardiac death (SCD), HR 0.72, 95% CI 0.58–0.89; ischemic cardiomyopathy, HR 1.41, 95% CI 1.76–1.70; NYHA class at implantation, HR 1.38, 95% CI 1.17–1.62; baseline left ventricle ejection fraction (EF), HR 0.97, 95% CI 0.96–0.98; severe mitral regurgitation, HR 1.38; 95% CI 1.08–1.75; baseline NT-proBNP concentration, HR 1.00, 95% CI 1.00–1.00; and creatinine level, HR 1.00, 95% CI 1.00–1.01. Conclusions In a real-life patient population with CRT only 13.5% survived over 10 years since device implantation. Independent predictors for death within 10 years since CRT implantation were older age, male sex, secondary prevention of SCD, ischemic and more advanced heart failure along with renal impairment. Funding Acknowledgement Type of funding sources: None.

The effect of three major co‐morbidities on quality of life and outcome of patients with heart failure with reduced ejection fraction

AimsDiabetes mellitus, chronic obstructive pulmonary disease, and chronic kidney disease are prevalent in patients with heart failure with reduced ejection fraction (HFrEF). We have analysed the impact of co‐morbidities on quality of life (QoL) and outcome.Methods and resultsA total of 397 patients (58.8 ± 11.0 years, 73.6% with New York Heart Association functional class ≥3) with stable advanced HFrEF were followed for a median of 1106 (inter‐quartile range 379–2606) days, and 68% of patients (270 patients) experienced an adverse outcome (death, urgent heart transplantation, and implantation of mechanical circulatory support). Chronic obstructive pulmonary disease was present in 16.4%, diabetes mellitus in 44.3%, and chronic kidney disease in 34.5% of patients; 33.5% of patients had none, 40.0% had one, 21.9% had two, and 3.8% of patient had three co‐morbidities. Patients with more co‐morbidities reported similar QoL (assessed by Minnesota Living with Heart Failure Questionnaire, 45.46 ± 22.21/49.07 ± 21.69/47.52 ± 23.54/46.77 ± 23.60 in patients with zero to three co‐morbidities, P for trend = 0.51). Multivariable regression analysis revealed that furosemide daily dose, systolic blood pressure, New York Heart Association functional class, and body mass index, but not the number of co‐morbidities, were significantly (P < 0.05) associated with QoL. Increasing co‐morbidity burden was associated with worse survival (P < 0.0001), lower degree of angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker treatment (P = 0.001), and increasing levels of BNP (mean of 685, 912, 1053, and 985 ng/L for patients with zero to three co‐morbidities, P for trend = 0.008) and cardiac troponin (sm‐cTnI, P for trend = 0.0496), which remained significant (P < 0.05) after the adjustment for left ventricular ejection fraction, left ventricular end‐diastolic diameter, right ventricular dysfunction grade, body mass index, and estimated glomerular filtration rate.ConclusionsIn stable advanced HFrEF patients, co‐morbidities are not associated with impaired QoL, but negatively affect the prognosis both directly and indirectly through lower level of HF pharmacotherapy and increased myocardial stress and injury.

Abstract 16824: Circulating Microvesicles in Heart Failure Patients Prior to, and Following LVAD Implantation

Introduction: Elevated levels of circulating endothelial and platelet (EMV and PMV) microvesicles are associated with endothelial dysfunction and thrombosis/inflammation, respectively. EMVs and PMVs are elevated in patients with heart failure with reduced ejection fraction (HFrEF) and are associated with clinical outcomes. We sought to characterize longitudinal changes in EMV and PMV following LVAD implantation in these patients. Methods: Blood samples were obtained from patients with advanced HFrEF (59±9years, N=9 males) during an invasive hemodynamic assessment with Swan-Ganz catheterization 2.7±4.1 and 4.3±1.3 months prior to, and following CF-LVAD implantation, respectively. Circulating concentrations of total MV, EMVs (CD31+) and PMVs (CD42b+) were determined by flow cytometry. Results: Demographics and hemodynamics pre- and post-LVAD implantation are displayed in the table . Prior to LVAD, four patients were on inotropes. Six patients received a Heartware VAD, and four patients received a Heartmate 3 VAD. As demonstrated in the figure , there was a significant reduction in total MV concentration, as well as EMVs and PMVs following LVAD implantation. Conclusion: Circulating concentrations EMVs and PMVs decline significantly in HFrEF patients following LVAD implantation. These findings are indicative of improvements in both endothelial function and thrombotic/inflammatory state associated with the heart-failure syndrome.