Propensity score-based analysis of 30-day survival in cardiogenic shock patients supported with different microaxial left ventricular assist devices.

BACKGROUND AND METHODS: Microaxial left ventricular assist devices are used increasingly for treating cardiogenic shock. We compared the short-term outcome of patients supported with different microaxial devices for cardiogenic shock. A retrospective propensity score-adjusted analysis was performed in cardiogenic shock patients treated with either the Impella CP (n = 64) or the Impella 5.0/5.5 (n = 62) at two tertiary cardiac care centers between 1/14 and 12/19. RESULTS: Patients in the Impella CP group were significantly older (69.6 ± 10.7 vs. 58.7 ± 11.9 years, p = .001), more likely in INTERMACS profile 1 (76.6% vs. 50%, p = .003) and post-C-reactive protein (CPR) (36% vs. 13%, p = .006). The median support time was 2.0 days [0.0, 5.3] in the CP group vs. 8.5 days [4.3, 15.8] in the 5.0/5.5 group (p < .001). The unadjusted 30-day survival was significantly higher in the Impella 5.0/5.5 group (58% vs. 36%, p = .021, odds ratio [OR] for 30-day survival on Impella 5.0/5.5 was 3.68 [95% confidence interval [CI]: [1.46-9.90]], p = .0072). After adjustment, the 30-day survival was similar for both devices (OR: 1.23, 95% CI: [0.34-4.18], p = .744). Lactate levels above 8 mmol/L and preoperative CPR were associated with a significant mortality increase in both cohorts (OR: 10.7, 95% CI: [3.45-47.34], p < .001; OR: 13.2, 95% CI: [4.28-57.89], p < .001, respectively). CONCLUSION: Both Impella devices offer a similar effect with regard to survival in cardiogenic shock patients. Preoperative CPR or lactate levels exceeding 8 mmol/L immediately before implantation have a poor prognosis on Impella CP and Impella 5.0/5.5.

Mode-of-action of the PROPELLA concept in fulminant myocarditis.

AIMS: Haemodynamic load induces cardiac remodelling via mechano-transduction pathways, which can further trigger inflammatory responses. We hypothesized that particularly in an inflammatory disorder such as myocarditis, a therapeutic strategy is required which, in addition to providing adequate circulatory support, unloads the left ventricle, decreases cardiac wall stress, and mitigates inflammatory responses. METHODS AND RESULTS: Axial flow pumps such as the Impella systems comply with these requirements. Here, we report a potential mode-of-action of prolonged Impella support (PROPELLA concept) in fulminant myocarditis, including a decrease in cardiac immune cell presence, and integrin α1, α5, α6, α10 and ß6 expression during unloading. CONCLUSION: PROPELLA may provide benefits beyond its primary function of mechanical circulatory support in the form of additional disease-altering effects, which may contribute to enhanced myocardial recovery/remission in patients with chronic fulminant myocarditis.

The CardioMEMS system in the clinical management of end-stage heart failure patients: three case reports.

BACKGROUND: Recent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients' therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status. CASE PRESENTATION: We present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor (ARNI, Sacubitril-Valsartan) on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization. CONCLUSIONS: Our case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.

Complexity of pathomechanisms leading to diastolic heart failure in diabetes mellitus - potential field for therapeutic interventions?

Advanced glycation end products (AGE) have been implicated in diabetes associated complications. They have been suggested as potential mediators in the progression of diabetic heart failure and as a potential target for treatment. Brunvand et al. now provided evidence in that the suggested causal relationship between AGE and diastolic myocardial dysfunction cannot be confirmed in children with type 1 diabetes. The early signs of diastolic myocardial impairment were associated with higher BMI, but not with HbA1c levels. Furthermore, higher serum levels of MG-H1 and increased arterial stiffness were not significantly associated with diastolic dysfunction. The lack of association argues against an essential role of AGEs. This sobering finding does not support the potential to treat diastolic dysfunction by reduction approaches AGE in type 1 diabetic patients. Further pathogenic mechanisms involved in diabetic cardiomyopathy, such as alterations of calcium metabolism, or remodeling of the extracellular matrix, and intramyocardial inflammation may be further promising therapeutic targets.

High-density lipoproteins reduce endothelial-to-mesenchymal transition.

OBJECTIVE: Endothelial-to-mesenchymal transition is an inflammation-induced process by which endothelial cells can transdifferentiate into fibroblasts. Based on the endothelial-protective and antifibrotic effects of high-density lipoproteins (HDL), we aimed to investigate whether HDL can reduce endothelial-to-mesenchymal transition. APPROACH AND RESULTS: Therefore, human aortic endothelial cells were stimulated with the profibrotic factor transforming growth factor (TGF)-ß1 in the presence or absence of HDL. Their impact on the transition of endothelial cells to mesenchymal-like cells was analyzed. Phase contrast microscopy demonstrated that HDL abrogated the TGF-ß1-induced spindle-shape morphology in human aortic endothelial cells. Furthermore, HDL decreased the TGF-ß1-mediated induction of α-smooth muscle actin expression and concomitant loss in endothelial cadherin expression, as shown by immunofluorescence staining and flow cytometry. In addition, HDL decreased the TGF-ß1-induced collagen deposition in human aortic endothelial cells involving the scavenger receptor class B, type 1 and downstream phosphatidyl inositol-3-kinase following the findings that the HDL-mediated reduction was abrogated by scavenger receptor class B, type 1 siRNA knockdown and phosphatidyl inositol-3-kinase inhibition, respectively. The HDL-mediated reduction in endothelial-to-mesenchymal transition was associated with an induction of the inhibitory Smad, Smad 7. CONCLUSIONS: We provide the first in vitro evidence that the endothelial-protective and antifibrotic effects of HDL include the reduction in endothelial-to-mesenchymal transition.

Postprocedural radial artery occlusion rate using a sheathless guiding catheter for left ventricular endomyocardial biopsy performed by transradial approach.

BACKGROUND: For coronary interventions the arterial access via the radial artery is associated with fewer vascular access site complications, and has been shown to reduce major bleeding when compared to the femoral approach. But the endomyocardial biopsy (EMB) approach is usually done by a transfemoral or cervical access known to be associated with an increased risk of artery puncture and its potential complications (i.e., false aneurysm, artery-venous fistula) and needs post-procedural immobilization. A transradial approach for EMBs is not standardized. The aim of our study is to validate safety and efficacy of the transradial access approach for left ventricular EMB, and to define patients eligible for a safe and successful procedure. METHODS AND RESULTS: We evaluated the transradial access using a 7.5 F sheathless multipurpose guiding catheter to obtain EMBs from the left ventricle (LV). 18 patients were included. The transradial success rate was 100% (18/18). There were no periprocedural cardiac complications. Immediate post-procedural ambulation could be achieved in all patients. Although radial artery pulse was confirmed by ultrasonic vascular Doppler after removal of the guide in 100% (18/18) of the patients, 50% (9/18) of the patients showed occlusion of the radial artery RAO) by duplex sonography proximal to the access site. 33% (3/9) of the patients in the RAO group and 11,1% (1/9) of the patients in the patent radial artery (RAP) group, respectively, experienced mild pain after the procedure in the right lower arm. Colour Doppler ultrasonography of the right radial artery performed 24 h after the procedure revealed radial occlusion in 50% (9/18) of the patients. The diameter of the radial artery was significantly smaller in the RAO group (p = 0,034), peak systolic velocity (PSV) of the right ulnar artery was significantly higher in the RAO group (p = 0.012). Peak systolic velocity of the opposite radial artery was significantly lower in the RAO group (p = 0,045). Gender, sex, diabetes, radial artery inner diameter ≤2.5 mm and lower peak systolic velocity of < 50 cm/s are predictors of RAO. CONCLUSION: The present study demonstrates the safety and efficacy of a transradial access for EMB using a highly hydrophilic sheathless guiding catheter.

Impaired Endothelial Regeneration Through Human Parvovirus B19-Infected Circulating Angiogenic Cells in Patients With Cardiomyopathy.

Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage.

High-density lipoproteins reduce palmitate-induced cardiomyocyte apoptosis in an AMPK-dependent manner.

Palmitate has been implicated in the induction of cardiomyocyte apoptosis via reducing the activity of 5' AMP-activated protein kinase (AMPK). We sought to evaluate whether high-density lipoproteins (HDLs), known for their cardioprotective features and their potential to increase AMPK activity, can reduce palmitate-induced cardiomyocyte apoptosis and whether this effect is AMPK-dependent. Therefore, cardiomyocytes were isolated from adult Wistar rat hearts via perfusion on a Langendorff-apparatus and cultured in free fatty acid-free BSA control medium or 0.5 mM palmitate medium in the presence or absence of HDL (5 µg protein/ml) with or without 0.1 µM of the AMPK-inhibitor compound S for the analysis of Annexin V/propidium, genes involved in apoptosis and fatty acid oxidation, and cardiomyocyte contractility. We found that HDLs decreased palmitate-induced cardiomyocyte apoptosis as indicated by a reduction in Annexin V-positive cardiomyocytes and an increase in Bcl-2 versus Bax ratio. Concomitantly, HDLs increased the palmitate-impaired expression of genes involved in fatty acid oxidation. Furthermore, HDLs improved the palmitate-impaired cardiomyocyte contractility. All effects were mediated in an AMPK-dependent manner, concluding that HDLs reduce palmitate-induced cardiomyocyte apoptosis, resulting in improved cardiomyocyte contractility through a mechanism involving AMPK.

Temporary extracorporeal life support: single-centre experience with a new concept.

OBJECTIVES: The combination of veno-arterial extracorporeal membrane oxygenation with a micro-axial flow pump (ECMELLA) is increasingly used for cardiogenic shock (CS) therapy. We report our experience with a novel single-artery access ECMELLA setup with either femoral (2.0) or jugular venous cannulation (2.1), respectively. METHODS: Data from 67 consecutive CS patients treated with ECMELLA 2.0 (n = 56) and 2.1 (n = 11) from December 2020 and December 2022 in a tertiary cardiac center were retrospectively analyzed. RESULTS: The mean age was 60.7 ± 11 years, 56 patients (84%) were male. CS aetiology was acute on chronic heart failure (n = 35, 52%), myocardial infarction (n = 13, 19.5%), postcardiotomy syndrome (n = 16, 24%) and myocarditis (n = 3, 4.5%). Preoperatively 31 patients (46%) were resuscitated, 53 (79%) were on a ventilator and 60 (90%) were on inotropic support. The median vasoactive inotropic score was 32, and the mean arterial lactate was 8.1 mmol/l. In 39 patients (58%), veno-arterial extracorporeal membrane oxygenation was explanted after a median ECMELLA support of 4 days. Myocardial recovery was achieved in 18 patients (27%), transition to a durable left ventricular assist device in 16 (24%). Thirty-three patients (n = 33; 49%) died on support (25 on ECMELLA and 8 on Impella after de-escalation), 9 (13%) of whom were palliated. Axillary access site bleeding occurred in 9 patients (13.5%), upper limb ischaemia requiring surgical revision in 3 (4.5%). Axillary site infection occurred in 6 cases (9%), and perioperative stroke in 10 (15%; 6 hemorrhagic, 4 thromboembolic). CONCLUSIONS: ECMELLA 2.0/2.1 is a feasible and effective therapy for severe CS. The single-artery cannulation technique is associated with a relatively low rate of access-related complications.

Left-ventricular unloading in extracorporeal cardiopulmonary resuscitation due to acute myocardial infarction - A multicenter study.

BACKGROUND: Guidelines advocate the use of extracorporeal cardio-pulmonary resuscitation with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in selected patients with cardiac arrest. Effects of concomitant left-ventricular (LV) unloading with Impella® (ECMELLA) remain unclear. This is the first study to investigate whether treatment with ECMELLA was associated with improved outcomes in patients with refractory cardiac arrest caused by acute myocardial infarction (AMI). METHODS: This study was approved by the local ethical committee. Patients treated with ECMELLA at three centers between 2016 and 2021 were propensity score (PS)-matched to patients receiving VA-ECMO based on age, electrocardiogram rhythm, cardiac arrest location and Survival After Veno-Arterial ECMO (SAVE) score. Cox proportional-hazard and Poisson regression models were used to analyse 30-day mortality rate (primary outcome), hospital and intensive care unit (ICU) length of stay (LOS) (secondary outcomes). Sensitivity analyses on patient demographics and cardiac arrest parameters were performed. RESULTS: 95 adult patients were included in this study, out of whom 34 pairs of patients were PS-matched. ECMELLA treatment was associated with decreased 30-day mortality risk (Hazard Ratio [HR] 0.53 [95% Confidence Interval (CI) 0.31-0.91], P = 0.021), prolonged hospital (Incidence Rate Ratio (IRR) 1.71 [95% CI 1.50-1.95], P < 0.001) and ICU LOS (IRR 1.81 [95% CI 1.57-2.08], P < 0.001). LV ejection fraction significantly improved until ICU discharge in the ECMELLA group. Especially patients with prolonged low-flow time and high initial lactate benefited from additional LV unloading. CONCLUSIONS: LV unloading with Impella® concomitant to VA-ECMO therapy in patients with therapy-refractory cardiac arrest due to AMI was associated with improved patient outcomes.

Nerve growth factor promotes cardiac repair following myocardial infarction.

RATIONALE: Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated. OBJECTIVE: To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI). METHODS AND RESULTS: Immunostaining for NGF and TrkA was performed on heart samples from humans deceased of MI or unrelated pathologies. To study the post-MI functions of endogenous NGF, a NGF-neutralizing antibody (Ab-NGF) or nonimmune IgG (control) was given to MI mice. To investigate the NGF therapeutic potential, human NGF gene or control (empty vector) was delivered to the murine periinfarct myocardium. Results indicate that NGF is present in the infarcted human heart. Both cardiomyocytes and endothelial cells (ECs) possess TrkA, which suggests NGF cardiovascular actions in humans. In MI mice, Ab-NGF abrogated native reparative angiogenesis, increased EC and cardiomyocyte apoptosis and worsened cardiac function. Conversely, NGF gene transfer ameliorated EC and cardiomyocyte survival, promoted neovascularization and improved myocardial blood flow and cardiac function. The prosurvival/proangiogenic Akt/Foxo pathway mediated the therapeutic benefits of NGF transfer. Moreover, NGF overexpression increased stem cell factor (the c-kit receptor ligand) expression, which translated in higher myocardial abundance of c-kit(pos) progenitor cells in NGF-engineered hearts. CONCLUSIONS: NGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.

Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis.

AIM: The acute phase of a coxsackievirus 3 (CVB3)-induced myocarditis involves direct toxic cardiac effects and the systemic activation of the immune system, including the cardiosplenic axis. Consequently, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome pathway is activated, which plays a role in disease pathogenesis and progression. The anti-inflammatory drug colchicine exerts its effects, in part, via reducing NLRP3 activity, and has been shown to improve several cardiac diseases, including acute coronary syndrome and pericarditis. The aim of the present study was to evaluate the potential of colchicine to improve experimental CVB3-induced myocarditis. METHODS AND RESULTS: C57BL6/j mice were intraperitoneally injected with 1 × 105 plaque forming units of CVB3. After 24 h, mice were treated with colchicine (5 µmol/kg body weight) or phosphate-buffered saline (PBS) via oral gavage (p.o.). Seven days post infection, cardiac function was haemodynamically characterized via conductance catheter measurements. Blood, the left ventricle (LV) and spleen were harvested for subsequent analyses. In vitro experiments on LV-derived fibroblasts (FB) and HL-1 cells were performed to further evaluate the anti-(fibro)inflammatory and anti-apoptotic effects of colchicine via gene expression analysis, Sirius Red assay, and flow cytometry. CVB3 + colchicine mice displayed improved LV function compared with CVB3 + PBS mice, paralleled by a 4.7-fold (P < 0.01) and 1.7-fold (P < 0.001) reduction in LV CVB3 gene expression and cardiac troponin-I levels in the serum, respectively. Evaluation of components of the NLRP3 inflammasome revealed an increased percentage of apoptosis-associated speck-like protein containing a CARD domain (ASC)-expressing, caspase-1-expressing, and interleukin-1ß-expressing cells in the myocardium and in the spleen of CVB3 + PBS vs. control mice, which was reduced in CVB3 + colchicine compared with CVB3 + PBS mice. This was accompanied by 1.4-fold (P < 0.0001), 1.7-fold (P < 0.0001), and 1.7-fold (P < 0.0001) lower numbers of cardiac dendritic cells, natural killer cells, and macrophages, respectively, in CVB3 + colchicine compared with CVB3 + PBS mice. A 1.9-fold (P < 0.05) and 4.6-fold (P < 0.001) reduced cardiac gene expression of the fibrotic markers, Col1a1 and lysyl oxidase, respectively, was detected in CVB3 + colchicine mice compared with CVB3 + PBS animals, and reflected by a 2.2-fold (P < 0.05) decreased Collagen I/III protein ratio. Colchicine further reduced Col3a1 mRNA and collagen protein expression in CVB3-infected FB and lowered apoptosis and viral progeny release in CVB3-infected HL-1 cells. In both CVB3 FB and HL-1 cells, colchicine down-regulated the NLRP3 inflammasome-related components ASC, caspase-1, and IL-1ß. CONCLUSIONS: Colchicine improves LV function in CVB3-induced myocarditis, involving a decrease in cardiac and splenic NLRP3 inflammasome activity, without exacerbation of CVB3 load.

Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection.

BACKGROUND: In a phase 1 study, we investigated whether interferon beta reduced endothelial damage in patients with cardiac persistence of human parvovirus B19 (B19V) infection. METHODS AND RESULTS: In vitro, B19V infected cultivated endothelial cells (ECs), which led to a reduction in their viability (P = .007). Interferon beta suppressed B19V replication by 63% (P = .008) in ECs and increased their viability (P = .021). Circulating mature apoptotic ECs (CMAECs [CD45(-)CD146(+) cells expressing von Willebrand factor and annexin V]) and circulating progenitor cells (CPCs [CD34(+)KDR(+) cells]) were quantified by flow cytometry in 9 symptomatic patients with cardiac B19V infection before and after 6 months of interferon beta therapy (16 MU) and were compared to levels in 9 healthy control subjects. Endothelial dysfunction was measured using flow-mediated dilatation of the forearm. Patients with B19V persistence had significantly higher (P = .04) levels of CMAECs than did control subjects, which normalized after treatment (mean +/- standard deviation, 0.06% +/-0.08% vs 0.01% +/- 0.006%; P = .008). Similar improvement was shown for flow-mediated dilatation (P = .04) in the treatment group only (P = .017 for the comparison with untreated patients with B19V persistence n = 5). There were significantly higher numbers of CPCs in patients with B19V persistence before therapy (mean +/- standard deviation, 0.04% +/- 0.05% vs 0.01% +/- 0.004%; P = .02; than in control subjects, which normalized after treatment (P = .03). CONCLUSION: Thus, we present (for the first time, to our knowledge) a modulation of virally induced chronic endothelial damage-specifically, EC apoptosis and endothelial regeneration.

The "TIDE"-Algorithm for the Weaning of Patients With Cardiogenic Shock and Temporarily Mechanical Left Ventricular Support With Impella Devices. A Cardiovascular Physiology-Based Approach.

Objectives: Mechanical circulatory support (MCS) is often required to stabilize therapy-refractory cardiogenic shock patients. Left ventricular (LV) unloading by mechanical ventricular support (MVS) via percutaneous devices, such as with Impella® axial pumps, alone or in combination with extracorporeal life support (ECLS, ECMELLA approach), has emerged as a potential clinical breakthrough in the field. While the weaning from MCS is essentially based on the evaluation of circulatory stability of patients, weaning from MVS holds a higher complexity, being dependent on bi-ventricular function and its adaption to load. As a result of this, weaning from MVS is mostly performed in the absence of established algorithms. MVS via Impella is applied in several cardiogenic shock etiologies, such as acute myocardial infarction (support over days) or acute fulminant myocarditis (prolonged support over weeks, PROPELLA). The time point of weaning from Impella in these cohorts of patients remains unclear. We here propose a novel cardiovascular physiology-based weaning algorithm for MVS. Methods: The proposed algorithm is based on the experience gathered at our center undergoing an Impella weaning between 2017 and 2020. Before undertaking a weaning process, patients must had been ECMO-free, afebrile, and euvolemic, with hemodynamic stability guaranteed in the absence of any inotropic support. The algorithm consists of 4 steps according to the acronym TIDE: (i) Transthoracic echocardiography under full Impella-unloading; (ii) Impella rate reduction in single 8-24 h-steps according to patients hemodynamics (blood pressure, heart rate, and ScVO2), including a daily echocardiographic assessment at minimal flow (P2); (iii) Dobutamine stress-echocardiography; (iv) Right heart catheterization at rest and during Exercise-testing via handgrip. We here present clinical and hemodynamic data (including LV conductance data) from paradigmatic weaning protocols of awake patients admitted to our intensive care unit with cardiogenic shock. We discuss the clinical consequences of the TIDE algorithm, leading to either a bridge-to-recovery, or to a bridge-to-permanent LV assist device (LVAD) and/or transplantation. With this protocol we were able to wean 74.2% of the investigated patients successfully. 25.8% showed a permanent weaning failure and became LVAD candidates. Conclusions: The proposed novel cardiovascular physiology-based weaning algorithm is based on the characterization of the extent and sustainment of LV unloading reached during hospitalization in patients with cardiogenic shock undergoing MVS with Impella in our center. Prospective studies are needed to validate the algorithm.

First in man evaluation of a novel circulatory support device: Early experience with the Impella 5.5 after CE mark approval in Germany.

BACKGROUND: The Abiomed Impella 5.5 (Danvers, MA) is a newly developed axial flow transaortic cardiac support device mounted on a 9 Fr steering catheter with a 21 Fr pump cannula. Impella 5.5 is intended for longer use and was approved for 30 days in 2018. This study evaluated the first-in-man series at six high-volume mechanical circulatory support centers in Germany after CE approval. METHODS: The first 46 consecutive patients worldwide underwent implantation in six German centers between March 2018 and September 2019 for post-CE approval evaluation. The primary end-point was 30 days and 90 days all-cause mortality. RESULTS: The mean age of patients was 59.0 ± 11.5 years, and 43 (93.4%) were men. Half of the patients had acute on chronic heart failure. The main indication for Impella 5.5 implantation was ischemic cardiomyopathy and acute myocardial infarction (47.8%). The mean support time was 15.5 ± 24.2 days (range 0-164, median 10 days (IQR = 7-19)) with a total of 712 patient-days on support. The 30 days and 90 days survival rates were 73.9% (95% CI: 63.3-88.9%) and 71.7% (95% CI: 60.7-87.1%), respectively. Additionally, 16 patients (34.8%) were weaned from the device for native heart recovery, and 19 (41.3%) were bridged to a durable device. Fifteen patients (32.6%) were mobilized to a chair, and 15 (32.6%) were ambulatory. We only noted one stroke and found no other thromboembolic complications. No aortic valve damage was observed in the study cohort. Finally, seven patients (15.2 %) had pump thrombosis, and nine (19.6 %) underwent device exchange. Sixteen patients (34.8 %) suffered from bleeding requiring transfusions during the whole treatment course. In ten patients (21.7%), the inflow cannula dislocated into the aortic root. CONCLUSIONS: The first version of the Impella 5.5 presents promising early outcomes for patients with acute heart failure and expands the spectrum of available devices. The adverse event profile is favorable for short-term devices. Dislocations have been addressed by design changes. With increasing experience with this device, our study suggests that the indications for use will expand to other cardiac shock etiologies and may improve myocardial recovery and survival in patients with cardiogenic shock.

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Case Report First-in-Man Method Description: Left Ventricular Unloading With iVAC2L During Veno-Arterial Extracorporeal Membrane Oxygenation: From Veno-Arterial Extracorporeal Membrane Oxygenation to ECMELLA to EC-iVAC®.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used in bi-ventricular failure with cardiogenic shock to maintain systemic perfusion. Nonetheless, it tends to increase left ventricular (LV) afterload and myocardial oxygen demand. In order to mitigate these negative effects on the myocardium, an Impella CP® (3.5 L/min Cardiac Output) can be used in conjunction with V-A ECMO (ECMELLA approach). We implemented this strategy in a patient with severe acute myocarditis complicated by cardiogenic shock. Due to a hemolysis crisis, Impella CP® had to be substituted with PulseCath iVAC2L®, which applies pulsatile flow to unload the LV. A subsequent improvement in LV systolic function was noted, with increased LV ejection fraction (LVEF), LV end-diastolic diameter (LVEDD) reduction, and a reduction in plasma free hemoglobin. This case documents the efficacy of iVAC2L in replacing Impella CP as a LV vent during V-A ECMO, with less hemolysis.

Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis.

AIMS: Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long-time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: SWR/J mice were infected with 5 × 104 plaque-forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8-fold (P < 0.05), 1.4-fold (P < 0.05), 3.2-fold (P < 0.01), and 2.1-fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone-treated vs. untreated CVB3-infected mice. In vitro, eplerenone led to 1.4-fold (P < 0.01) and 1.2-fold (P < 0.01) less CVB3-induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1-fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone-treated vs. untreated CVB3-infected HL-1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4-fold (P < 0.01) and 2.1-fold (P < 0.001) lower collagen content in the LV of eplerenone-treated vs. untreated CVB3-infected mice at Days 8 and 28, respectively. This resulted in an early and long-lasting improvement of LV dimension and function, as indicated by reduced LV end-systolic volume and end-diastolic volume, and an increase in LV contractility (dP/dtmax ) and LV relaxation (dP/dtmin ), respectively (P < 0.05). CONCLUSIONS: Early intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3-induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation-induced myocardial dysfunction. This may also have implications for coronavirus disease-19 therapy.

Prediction of survival of patients in cardiogenic shock treated by surgically implanted Impella 5+ short-term left ventricular assist device.

OBJECTIVES: Short-term mechanical circulatory support is a life-saving treatment for acute cardiogenic shock (CS). This multicentre study investigates the preoperative predictors of 30-day mortality in CS patients treated with Impella 5.0 and 5.5 short-term left ventricular assist devices. METHODS: Data of patients in CS (n = 70) treated with the Impella 5 (n = 63) and 5.5 (n = 7) in 2 centres in Berlin between October 2016 and October 2019 were collected retrospectively. RESULTS: CS was caused by acute myocardial infarction (n = 16), decompensated chronic heart failure (n = 41), postcardiotomy syndrome (n = 5) and acute myocarditis (n = 8). Before implantation 12 (17%) patients underwent cardiopulmonary resuscitation and 32 (46%) patients were ventilated. INTERMACS level 1, 2 and 3 was established in 35 (50%), 29 (41%) and 6 (9%) of patients, respectively. The mean preoperative lactate level was 4.05 mmol/l. The median support time was 7 days (IR= 4-15). In 18 cases, the pump was removed for myocardial recovery, in 22 cases, durable left ventricular assist devices were implanted, and 30 patients died on support. The overall 30-day survival was 51%. Statistical analysis showed that an increase in lactate per mmol/l [odds ratio (OR) 1.217; P = 0.015] and cardiopulmonary resuscitation before implantation (OR 16.74; P = 0.009) are predictors of 30-day survival. Based on these data, an algorithm for optimal short-term mechanical circulatory support selection is proposed. CONCLUSIONS: Impella treatment is feasible in severe CS. Severe organ dysfunction, as well as the level and duration of shock predict early mortality. An algorithm based on these parameters may help identify patients who would benefit from Impella 5+ support.

Role of left ventricular stiffness in heart failure with normal ejection fraction.

BACKGROUND: Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. METHODS AND RESULTS: Patients with HFNEF (n=70) and patients without heart failure symptoms (n=20) were enrolled. Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with decreased stroke volume and a leftward shift of pressure-volume loops during atrial pacing. CONCLUSIONS: Increased left ventricular stiffness contributed to increased end-diastolic pressure during handgrip exercise and decreased stroke volume during atrial pacing in patients with HFNEF. These data suggest that left ventricular stiffness modulates cardiac function in HFNEF patients and suggests that diastolic dysfunction with increased stiffness is a target for treating HFNEF.