Haemodynamic implications of VA-ECMO vs. VA-ECMO plus Impella CP for cardiogenic shock in a large animal model.

AIMS: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) with profound left ventricular (LV) failure is associated with inadequate LV emptying. To unload the LV, VA-ECMO can be combined with Impella CP (ECMELLA). We hypothesized that ECMELLA improves cardiac energetics compared with VA-ECMO in a porcine model of cardiogenic shock (CS). METHODS AND RESULTS: Land-race pigs (weight 70 kg) were instrumented, including a LV conductance catheter and a carotid artery Doppler flow probe. CS was induced with embolization in the left main coronary artery. CS was defined as reduction of ≥50% in cardiac output or mixed oxygen saturation (SvO2) or a SvO2 < 30%. At CS VA-ECMO was initiated and embolization was continued until arterial pulse pressure was <10 mmHg. At this point, Impella CP was placed in the ECMELLA arm. Support was maintained for 4 h. CS was induced in 15 pigs (VA-ECMO n = 7, ECMELLA n = 8). At time of CS MAP was <45 mmHg in both groups, with no difference at 4 h (VA-ECMO 64 mmHg ± 11 vs. ECMELLA 55 mmHg ± 21, P = 0.08). Carotid blood flow and arterial lactate increased from CS and was similar in VA-ECMO and ECMELLA [239 mL/min ± 97 vs. 213 mL/min ± 133 (P = 0.6) and 5.2 ± 3.3 vs. 4.2 ± 2.9 mmol/ (P = 0.5)]. Pressure-volume area (PVA) was significantly higher with VA-ECMO compared with ECMELLA (9567 ± 1733 vs. 6921 ± 5036 mmHg × mL/min × 10-3, P = 0.014). Total diureses was found to be lower in VA-ECMO compared with ECMELLA [248 mL (179-930) vs. 506 mL (418-2190); P = 0.005]. CONCLUSIONS: In a porcine model of CS, we found lower PVA, with the ECMELLA configuration compared with VA-ECMO, indicating better cardiac energetics without compromising systemic perfusion.

Immediate inflammatory response to mechanical circulatory support in a porcine model of severe cardiogenic shock.

BACKGROUND: In selected cases of cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is combined with trans valvular micro axial flow pumps (ECMELLA). Observational studies indicate that ECMELLA may reduce mortality but exposing the patient to two advanced mechanical support devices may affect the early inflammatory response. We aimed to explore inflammatory biomarkers in a porcine cardiogenic shock model managed with V-A ECMO or ECMELLA. METHODS: Fourteen landrace pigs had acute myocardial infarction-induced cardiogenic shock with minimal arterial pulsatility by microsphere embolization and were afterwards managed 1:1 with either V-A ECMO or ECMELLA for 4 h. Serial blood samples were drawn hourly and analyzed for serum concentrations of interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha, and serum amyloid A (SAA). RESULTS: An increase in IL-6, IL-8, and SAA levels was observed during the experiment for both groups. At 2-4 h of support, IL-6 levels were higher in ECMELLA compared to V-A ECMO animals (difference: 1416 pg/ml, 1278 pg/ml, and 1030 pg/ml). SAA levels were higher in ECMELLA animals after 3 and 4 h of support (difference: 401 ng/ml and 524 ng/ml) and a significant treatment-by-time effect of ECMELLA on SAA was identified (p = 0.04). No statistical significant between-group differences were observed in carotid artery blood flow, urine output, and lactate levels. CONCLUSIONS: Left ventricular unloading with Impella during V-A ECMO resulted in a more extensive inflammatory reaction despite similar end-organ perfusion.

Impact of Impella RP Versus Vasoactive Treatment on Right and Left Ventricular Strain in a Porcine Model of Acute Cardiogenic Shock Induced by Right Coronary Artery Embolization.

Background The response of the left ventricle to cardiogenic shock (CS) caused by right ventricular (RV) infarction and the effect of treatment with either vasoactive treatment or Impella RP are not well described. We sought to determine RV and left ventricular longitudinal strain (LS) by echocardiography after initiation of either Impella RP or vasoactive treatment for CS induced by right coronary artery embolization. Methods and Results CS was induced with microsphere embolization in the right coronary artery in 20 pigs. Shock was defined as a reduction in cardiac output of ≥50% and/or an SvO2 <30%. At the time of CS either Impella RP or vasoactive treatment (norepinephrine and milrinone) was initiated. Echocardiography and conductance measures were obtained at baseline, when CS was present, and 30, 90, and 180 minutes after induction of CS. Of 20 animals, 14 completed the protocol and were treated with either vasoactive treatment (n=7) or Impella RP (n=7); 6 animals died (3 in each group). In the RV there was a significantly higher LS with the vasoactive treatment compared with Impella RP (-7.6% [4.5] to -6.0% [5.2] vs -4.5% [6.6] to -14.2% [10.6]; P<0.006). Left ventricular LS improved with both treatments compared with shock, but with a larger effect (-9.4% [3.2] to -17.9% [3.6]) on LS with vasoactive treatment than Impella RP (-9.8% [3.1] to -12.3% [4.6]; P<0.001). We found a significant correlation between stroke work and RV LS (r=-0.60, P<0.001) and left ventricular LS (r=-0.62, P<0.001). Conclusions We found significantly higher hemodynamic effects with vasoactive treatment compared with Impella RP in both the RV and left ventricular but at a cost of increased stroke work.

Pressure-flow responses to exercise in aortic stenosis, mitral regurgitation and diastolic dysfunction.

BACKGROUND: Haemodynamic exercise testing is important for evaluating patients with dyspnoea on exertion and preserved ejection fraction. Despite very different pathologies, patients with pressure (aortic stenosis (AS)) and volume (mitral regurgitation (MR)) overload and diastolic dysfunction after recent acute myocardial infarction (AMI) reach similar filling pressure levels with exercise. The pressure-flow relationships (the association between change in cardiac output (∆CO) and change in pulmonary arterial wedge pressure (∆PAWP) may provide insight into haemodynamic adaptation to exercise in these groups. METHODS AND RESULTS: One hundred sixty-eight subjects aged >50 years with a left ventricular ejection fraction of ≥50% underwent invasive exercise testing. They were enrolled in four different studies: AS (40 patients), AMI (52 patients), MR (43 patients) and 33 healthy subjects. Haemodynamic data were measured at rest, at 25 W, 75 W and at peak exercise. In all groups, PAWP increased with exercise. The greatest increase was observed in patients with AMI (from 12.7±3.9 mm Hg to 33.1±8.2 mm Hg, p<0.0001) and patients with AS (from 11.8±3.9 mm Hg to 31.4±6.1 mm Hg, p<0.0001), and the smallest was observed in healthy subjects (from 8.3±2.4 mm Hg to 21.1±7.5 mm Hg, p<0.0001). In all groups, the relative pressure increase was greatest at the beginning of the exercise. CO increased most in healthy patients (from 5.3±1.1 to 16.0±3.0 L/min, p<0.0001) and least in patients with AS (from 5.3±1.2 L/min to 12.4±2.6 L/min, p<0.0001). The pressure-flow relationships (∆PAWP/∆CO) and differed among groups (p=0.02). In all groups, the pressure-flow relationship was steepest in the initial phase of the exercise test. The AMI and AS groups (2.3±1.2 mm Hg/L/min and 3.0±1.3 mm Hg/L/min, AMI and AS, respectively) had the largest overall pressure-flow relationship; the healthy group had the smallest initially and at peak exercise (1.3±1.1 mm Hg/L/min) followed by MR group (1.9±1.4 mm Hg/L/min). CONCLUSION: The pressure-flow relationship was steepest in the initial phase of the exercise test in all groups. The pressure-flow relationship differs between groups. TRIAL REGISTRATION NUMBERS: NCT01974557, NCT01046838, NCT02961647 and NCT02395107.

The effect of empagliflozin on contractile reserve in heart failure: Prespecified sub-study of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether sodium-glucose co-transporter-2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction. METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤ 40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS (adjusted mean absolute change, empagliflozin vs placebo, 0.7% [95% confidence interval {CI} -0.5 to 2.0, P = .25]) or LVEF (adjusted mean absolute change, empagliflozin vs placebo, 2.2% [95% CI -1.4 to 5.8, P = .22]) from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level (coefficient -24 accelerometer counts [95% CI -46 to -1.8, P = .03]). CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HF and reduced ejection fraction.

Effect of Empagliflozin on Blood Volume Redistribution in Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis From the Empire HF Randomized Clinical Trial.

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<0.0001). The effect of empagliflozin was consistent across subgroup analysis. 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.

Biventricular Compared to Left Ventricular Impella and Norepinephrine Support in a Porcine Model of Severe Cardiogenic Shock.

Contemporary management of cardiogenic shock (CS) with vasopressors is associated with increased cardiac workload and despite the use of unloading devices such as the Impella pump, concomitant vasopressors are often necessary. Therefore, we compared if cardiac workload could be reduced and end-organ perfusion preserved with biventricular support (Bipella) compared to ImpellaCP and norepinephrine in pigs with left ventricular (LV) CS caused by left main coronary microembolization. Cardiac workload was calculated from heart rate × ventricular pressure-volume area obtained from conductance catheters placed in the LV and right ventricle (RV), whereas organ perfusion was measured from venous oxygen saturation in the pulmonary artery (SvO 2 ) and the kidney- and the cerebral vein. A cross-over design was used to access the difference after 30 minutes of ImpellaCP and norepinephrine 0.1 µg/kg/min versus Bipella for 60 minutes. Bipella treatment reduced LV workload ( p = 0.0078) without significant difference in RV workload from ImpellaCP and norepinephrine, however a decrease in SvO 2 (49[44-58] vs . 66[63-73]%, p = 0.01) and cerebral venous oxygen saturations (62[48-66] vs . 71[63-77]%, p = 0.016) was observed during Bipella compared to ImpellaCP and norepinephrine. We conclude that Bipella reduced LV workload but did not preserve end-organ perfusion compared to ImpellaCP and norepinephrine in short-term LV CS.

Hemodynamic Determinants of Activity Measured by Accelerometer in Patients With Stable Heart Failure.

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).

Impella RP Versus Pharmacologic Vasoactive Treatment in Profound Cardiogenic Shock due to Right Ventricular Failure.

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.

Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial.

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.

Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.

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.

Impact of concomitant vasoactive treatment and mechanical left ventricular unloading in a porcine model of profound cardiogenic shock.

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 < 0.0001], and SvO2 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 < 0.0001] due to increase in potential energy (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.