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Background: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the SGLT2 (sodium–glucose cotransporter-2) favorably affects SBV. We investigated the effect of empagliflozin on estimated SBV in patients with heart failure and reduced ejection fraction compared with placebo. Methods: This was a post hoc analysis of an investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in estimated SBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment. Results: Patients with heart failure and reduced ejection fraction, mean age, 57 years and mean ejection fraction 27%, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on estimated SBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (−198.4 mL [95% CI, −317.4 to −79.3] P =0.001), a 9% decrease. The decrease in estimated SBV by empagliflozin was significantly correlated with the decrease in PCWP ( R =−0.33, P Conclusions: Empagliflozin treatment significantly reduced SBV compared with placebo after 12 weeks of treatment in patients with stable chronic heart failure and reduced ejection fraction during sub maximal exercise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03198585.

The aim was to translationally compare a pharmacologic strategy versus treatment with the Impella RP in profound RV cardiogenic shock (CS). The pigs were allocated to either vasoactive therapy with norepinephrine (0.10 μg/kg/min) for the first 30 min, supplemented by an infusion of milrinone (0.4 μg/kg/min) for additional 150 min, or treatment with the Impella RP device for 180 min. Total RV workload (Pressure-volume-area × heart rate*103(mmHg/min)) remained unaffected upon treatment with the Impella RP and increased in the vasoactive group (CS 179[147;228] to norepinephrine 268[247;306](p = 0.002 compared to Impella RP) and norepinephrine + milrinone 366[329;422] (p = 0.002 compared to Impella RP). A trend towards higher venous cerebral oxygen saturation was observed with norepinephrine than Impella RP (Impella RP 51[47;61]% vs norepinephrine 62[57;71]%; p = 0.07), which became significantly higher with the addition of milrinone (Impella RP 45[32;63]% vs norepinephrine + milrinone 73[66;81]%; p = 0.002). The Impella RP unloaded the failing RV. In contrast, vasoactive treatment led to enhanced cerebral venous oxygen saturation.

Objectives: This study examined the link between accelerometer recordings and cardiac pathophysiology measured with right heart cauterization at rest and with exercise in patients with HFrEF. Background: Patient-worn accelerometers are increasingly being used in patients with heart failure with reduced ejection fraction (HFrEF) to assess activity and serve as surrogate endpoints in heart failure trials. Methods: Physical average daily activity (PADA) and total average daily activity according to accelerometer units were assessed in 63 patients (mean age 58 ± 10 years; mean ejection fraction 26% ± 4%). Patients underwent hemodynamic exercise testing and accelerometry. Patients were divided according to PADA in PADALow and PADAHigh activity level groups based on median counts per minute of physical activity. Results: Patients in the PADALow group were older and more frequently treated with diuretics. At rest, the PADALow group was characterized by a lower cardiac index (2.2 ± 0.4 L/min/m2 vs 2.4 ± 0.4 L/min/m2; P = 0.01) and stroke volume (70 ± 19 mL vs 81 ± 17 mL; P = 0.02) but not pulmonary capillary wedge pressure (12 ± 5 mm Hg vs 11 ± 5 mm Hg; P = 0.3). The PADALow group reached a lower cardiac index (4.8 ± 1.7 L/min/m2 vs 6.6 ± 1.7 L/min/m2; P < 0.001) but not in pulmonary capillary wedge pressure (31 ± 12 mm Hg vs 27 ± 8 mm Hg; P = 0.2) at peak exercise. The attenuated increase was associated with an attenuated increase in stroke volume (94 ± 32 mL vs 121 ± 29 mL; P < 0.001) rather than a reduced increase in heart rate (42 ± 23 beats/min vs 52 ± 21 beats/min; P = 0.07). PADA and total average daily accelerometer units were associated with patient-reported functional impairment according to the Kansas City Cardiomyopathy Questionnaire but not with New York Heart Association functional class. Conclusions: Among stable ambulatory patients with HFrEF, lower daily activity is associated with poorer cardiac index reserve and reduced cardiac index during exercise. (Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction; NCT03198585)

Background Patient-worn accelerometer is increasingly used in patients with heart failure and reduced ejection fraction (HFrEF) to assess daily activity and and as surrogate endpoint. We examined the association between cardiac physiology and daily activity by patient-worn accelerometer recordings in stable HFrEF patients. Methods In this descriptive study, physical average daily accelerometer units (PADA) and total average daily accelerometer unit (TADA) were assessed by a accelerometer recordings. Sixty three stable ambulatory patients with HFrEF, mainly men (92%), mean age 58±10 years, and ejection-fraction 26±4% underwent hemodynamic exercise testing, and accelerometry (Table 1). Patients were divided by PADA in a low and high activity level groups based on counts per minute physical activity. Results Patients in the low activity group were older and more frequently treated with diuretics. At rest, the low activity group was characterized by a lower cardiac index (CI) (2.2±0.4 vs. 2.4±0.4 l/min/m2, p=0.01), Stroke volume (SV) (70±19 vs. 81±17 ml, p=0.02) but not pulmonary capillary wedge pressure (PCWP) (12±5 vs. 11±5 mmHg, p=0.3) (Figure 1). Low activity group reached a lower CI (4.8±1.7 vs. 6.6±1.7 l/min/m2, p Conclusion Accelerometer-assessed activity in patients with HFrEF are associated with impairments in LV performance, SV reserve and cardiac output during exercise, to a greater extent than changes in arterial-venous O2 content difference or pulmonary vascular pressures. Accelerometer data may provide information about the functional status that we do not nessecary find in the widely used tools in both research and daily clinical practice. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the Danish Heart Foundation [grant numbers 17-R116-A7714-22076, 18-R124-A8573-22107]; Steno Diabetes Center Odense, Denmark [grant number 3363] and A.P. Møller Foundation for the Advancement of Medical Science [grant number 17-L-0339]. Table 1. Baseline and regression analysisFigure 1. Change in PCWP and CI by exercise

Background Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown. Methods This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5–10.0% (48–86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included. Discussion The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials. Trial registration Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27. Registered on 29 May 2017. ClinicalTrials.gov, NCT03198585. Registered on 26 June 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3474-5) contains supplementary material, which is available to authorized users.

Background: Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. Since the possibility to detect signs of acute myocardial deterioration at treatment initiation is not clarified, the objective of this study was to assess changes in GLS and biomarkers within the first 2 weeks of trastuzumab treatment. Methods: In a prospective cohort study, 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8%, GLS -19.9%, 40% hypertension) scheduled for trastuzumab treatment were included. Echocardiography and measurement of troponin and NT-proBrain-Natriuretic-Peptide were conducted before initiation of trastuzumab, at days 3, 7, and 14 and after 3, 6, and 9 months. Results: A significant deterioration in LVEF from 62.8% (SD±3.6) to 58.4% (SD±4.1) (p

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated. Objective: To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF. Design, Setting, and Participants: This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019. Interventions: Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks. Main Outcomes and Measures: Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness. Results: A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P =.04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P =.03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P =.04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P =.32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P =.03). Conclusions and Relevance: In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study. Trial Registration: ClinicalTrials.gov Identifier: NCT03198585.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation Unrestricted research grant from Abiomed Background No strong evidence exists regarding the treatment of cardiogenic shock (CS) caused by acute right ventricular (RV) failure which has mainly consisted of vasoactive drugs. There is expert agreement that treatment with the recently developed Impella RP is feasible, but no previous studies have compared vasoactive treatment strategies with the Impella RP in terms of cardiac unloading and end-organ perfusion. Hypothesis Treatment with the Impella RP device will be associated with lower RV myocardial workload (pressure-volume area) compared to vasoactive treatment strategies and can furthermore be achieved without compromising organ perfusion. Methods CS was induced by a stepwise injection of polyvinyl alcohol microspheres into the right coronary artery in twenty adult female Danish landrace pigs weighing 75-80 kg. After induction of CS, the pigs were allocated to one of the two interventions for 180 minutes: 1) vasoactive therapy comprised a continuous infusion of norepinephrine (0.1 µg/kg/min) for the first 30 minutes, supplemented by an infusion of milrinone (0.4 µg/kg/min) for the remaining 150 minutes or 2) immediate insertion of and treatment with the Impella RP. The results are presented as median [Q1;Q3]. Results Treatment with the Impella RP was associated with a lower RV workload compared to the vasoactive group, while no difference was observed with regards to left ventricular workload among intervention groups, Figure 1. Renal venous oxygen saturation increased to a similar degree following both interventions compared to the state of CS. A trend towards a higher cerebral venous oxygen saturation was observed with norepinephrine compared to Impella RP (Impella RP 51 [47;61] % vs Norepinephrine 62 [57;71] % ; p = 0.07), which became significantly higher with the addition of milrinone (Impella RP 45 [32;63] % vs Norepinephrine +Milrinone 73 [66;81] %; p = 0.002). Conclusion In this large animal model of profound CS caused by predominantly RV failure the Impella RP unloaded the failing RV. The vasoactive treatment, however, caused a higher cerebral venous oxygen saturation, while both interventions increased renal venous oxygen saturation to a similar degree. Abstract Figure 1

Background: Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. Objectives: This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. Methods: This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. Results: Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (−0.13 mm Hg/l/min/m2; 95% confidence interval: −1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (−2.40 mm Hg; 95% confidence interval: −3.96 to −0.84 mm Hg; p = 0.003), but not CI (−0.09 l/min/m2; 95% confidence interval: −0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. Conclusions: Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.

Background Concomitant vasoactive drugs are often required to maintain adequate perfusion pressure in patients with acute myocardial infarction (AMI) and cardiogenic shock (CS) receiving hemodynamic support with an axial flow pump (Impella CP). Objective To compare the effect of equipotent dosages of epinephrine, dopamine, norepinephrine, and phenylephrine on cardiac work and end-organ perfusion in a porcine model of profound ischemic CS supported with an Impella CP. Methods CS was induced in 10 pigs by stepwise intracoronary injection of polyvinyl microspheres. Hemodynamic support with Impella CP was initiated followed by blinded crossover to vasoactive treatment with norepinephrine (0.10 μg/kg/min), epinephrine (0.10 μg/kg/min), or dopamine (10 μg/kg/min) for 30 min each. At the end of the study, phenylephrine (10 μg/kg/min) was administered for 20 min. The primary outcome was cardiac workload, a product of pressure-volume area (PVA) and heart rate (HR), measured using the conductance catheter technique. End-organ perfusion was assessed by measuring venous oxygen saturation from the pulmonary artery (SvO2), jugular bulb, and renal vein. Treatment effects were evaluated using multilevel mixed-effects linear regression. Results All catecholamines significantly increased LV stroke work and cardiac work, dopamine to the greatest extend by 341.8 × 103 (mmHg × mL)/min [95% CI (174.1, 509.5), p 2 significantly improved during all catecholamines. Phenylephrine, a vasoconstrictor, caused a significant increase in cardiac work by 437.8 × 103 (mmHg × mL)/min [95% CI (297.9, 577.6), p p = 0.001), but no significant change in LV stroke work. Also, phenylephrine tended to decrease SvO2 (p = 0.063) and increased arterial lactate levels (p = 0.002). Conclusion Catecholamines increased end-organ perfusion at the expense of increased cardiac work, most by dopamine. However, phenylephrine increased cardiac work with no increase in end-organ perfusion.

Purpose To compare the effect of equipotent dosages of epinephrine, dopamine, norepinephrine, and phenylephrine on left ventricular (LV) work and end-organ perfusion in a porcine model of profound ischemic cardiogenic shock (CS) supported by Impella CP. Methods CS was induced in 10 pigs by stepwise intracoronary injection of microspheres. After CS was induced and Impella CP support initiated, animals were treated in a blinded crossover design with norepinephrine (0.10 µg/kg/min), epinephrine (0.10 µg/kg/min) or dopamine (10 µg/kg/min) for 30 minutes each. Phenylephrine (10 µg/kg/min) was given at the end of the study for 20 minutes. LV work was estimated using a conductance catheter. Main outcome measure was LV work estimated by pressure volume area (PVA) x heart rate. End-organ perfusion was evaluated by mixed venous oxygen saturation (SVO2) from the pulmonary artery and arterial lactate levels. Multilevel mixed-effects linear regression was used to evaluate treatment effect. Results All vasoactive drugs induced a significant increase in LV work, borderline for norepinephrine by 92.4 (mmHg*mL)*103/min ⦋95%CI(-1.1, 186), p=0.053)⦌. For all catecholamines, stroke work was significantly increased, but unchanged with phenylephrine, which on the other hand caused a significant increase in potential energy by 483 mmHg*mL ⦋95%CI(195, 772), p=0.001)⦌. SVO2 increased significantly with catecholamines and decreased borderline with phenylephrine by -9 %point ⦋95%CI(-19, 0.49), p=0.063)⦌ which also increased arterial lactate levels by 2.4 mmol/L ⦋95%CI(0.89, 3.92), p=0.002)⦌. There was a trend toward lower arterial lactate levels with norepinephrine by -1.53 mmol/L ⦋95%CI(-3.15, 0.09), p=0.064)⦌ Conclusion Catecholamines increased SVO2 but at the expense of increased LV work, least for norepinephrine and highest for dopamine (figure). Isolated vasoconstriction (phenylephrine) caused an increase in LV work, a decrease in SVO2 and increase in arterial lactate levels.

Background and aimThis study aimed to assess right ventricular (RV) function during cardiogenic shock due to acute left ventricular (LV) failure, including during LV unloading with Impella CP and an added moderate dose of norepinephrine.MethodsCardiogenic shock was induced by injecting microspheres in the left main coronary artery in 18 adult Danish Landrace pigs. Conductance catheters were placed in both ventricles and pressure-volume loops were recorded simultaneously.ResultsCardiogenic shock due to LV failure also impaired RV performance, which was partially restored during haemodynamic support with Impella CP, as demonstrated by changes in the ventriculo-arterial coupling (Ea/Ees ratio) (baseline (median [Q1;Q3]) 1.2 [1.1;1.6]), cardiogenic shock (3.0 [2.4;4.5]), Impella CP (2.1 [1.3;2.7]) (pBaseline vs CS< 0.0001, pCS vs Impella= 0.001)). Impella CP support also improved RV stroke work (SW) (cardiogenic shock 333 [263;530] vs Impella CP (830 [717;1121]) (p< 0.001). Moderate norepinephrine infusion concomitant with Impella CP further improved RV SW (Impella CP (818 [751;1065]) vs Impella CP+moderate norepinephrine (1231 [1142;1335]) (p= 0.01)) but at the expense of an increase in LV SW (Impella CP (858 [555;1392]) vs Impella CP+moderate norepinephrine (2101 [1024;2613]) (p= 0.04)).ConclusionsThe Impella CP provided efficient LV unloading, improved RV function, and end-organ perfusion. Moderate doses of norepinephrine during Impella support further improved RV function, but at the expense of an increase in SW of the failing LV.

Funding Acknowledgements The Danish Heart Foundation, Copenhagen (grant number: 14-R97-A5188-22839 and 15-R99-A5940). The Research Fond of the Region of Southern Denmark. Background Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. The possibility to detect signs of acute myocardial deterioration at treatment initiation is not thoroughly investigated. Accordingly, the aim of this study was to assess changes in GLS and biomarkers within the first two weeks of trastuzumab treatment. Methods In a prospective cohort study 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8% (SD ± 3.6), GLS -19.9% (SD ± 2.1), 40% hypertension) were included. Examinations including echocardiography and measurement of troponin T and NT-proBrain Natriuretic Peptide were conducted before initiation of trastuzumab, at day 3, 7 and 14 and after 3, 6 and 9 months. Results A significant deterioration in LVEF, GLS, s’, e’ septal and s’RV occurred during the 9 months study period and was proceed by significant changes in all these parameters within the first 14 days. After 14 days 12 patients (27%) had an increase in GLS ≥10 %, which was associated with significantly lower LVEF at nine month at 55.2% (SD ± 4.1) vs. 59.5% (SD ± 3.5) (p = 0.001) compared to patients with Conclusion In this cohort study deteriorations in key echocardiographic parameters were detected within the first two weeks of trastuzumab treatment, and an early 10 % increase in GLS was associated with a lower LVEF at nine months. Abstract P1533 Figure 1