Prediction of cardiac worsening through to cardiogenic shock in patients with acute heart failure.

AIMS: Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new-onset CS in patients hospitalized for AHF. METHODS AND RESULTS: Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow-up until death or discharge. WHF was defined by the RELAX-AHF-2 criteria. CS was defined as SCAI stages B-E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In-hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21-36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32-231.81, P < 0.001). Chronic kidney disease (OR 2.20, 95% CI 1.25-3.93, P = 0.007), logarithmized serum creatinine (OR 2.90, 95% CI 1.51-5.82, P = 0.002), cystatin c (OR 1.86, 95% CI 1.27-2.77, P = 0.002), tricuspid valve regurgitation (OR 2.08, 95% CI 1.11-3.94, P = 0.023) and logarithmized pro-adrenomedullin (OR 3.01, 95% CI 1.75-5.38, P < 0.001) were significant predictors of WHF. Chronic kidney disease (OR 3.17, 95% CI 1.16-9.58, P = 0.03), cystatin c (OR 1.88, 95% CI 1.00-3.53, P = 0.045), logarithmized pro-adrenomedullin (OR 2.90, 95% CI 1.19-7.19, P = 0.019), and tricuspid valve regurgitation (OR 10.44, 95% CI 2.61-70.00, P = 0.003) were significantly with new-onset CS. CONCLUSIONS: Half of patients admitted with AHF experience WHF or new-onset CS. Chronic kidney disease, tricuspid valve regurgitation, and elevated pro-adrenomedullin concentrations predict these events. They could potentially serve as early warning signs for further deterioration in AHF patients.

Sex-related differences in patients presenting with heart failure-related cardiogenic shock.

BACKGROUND: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of all CS cases. Nevertheless, there is a lack of evidence on sex-related differences in HF-CS, especially regarding use of treatment and mortality risk in women vs. men. This study aimed to investigate potential differences in clinical presentation, use of treatments, and mortality between women and men with HF-CS. METHODS: In this international observational study, patients with HF-CS (without acute myocardial infarction) from 16 tertiary-care centers in five countries were enrolled between 2010 and 2021. Logistic and Cox regression models were used to assess differences in clinical presentation, use of treatments, and 30-day mortality in women vs. men with HF-CS. RESULTS: N = 1030 patients with HF-CS were analyzed, of whom 290 (28.2%) were women. Compared to men, women were more likely to be older, less likely to have a known history of heart failure or cardiovascular risk factors, and lower rates of highly depressed left ventricular ejection fraction and renal dysfunction. Nevertheless, CS severity as well as use of treatments were comparable, and female sex was not independently associated with 30-day mortality (53.0% vs. 50.8%; adjusted HR 0.94, 95% CI 0.75-1.19). CONCLUSIONS: In this large HF-CS registry, sex disparities in risk factors and clinical presentation were observed. Despite these differences, the use of treatments was comparable, and both sexes exhibited similarly high mortality rates. Further research is necessary to evaluate if sex-tailored treatment, accounting for the differences in cardiovascular risk factors and clinical presentation, might improve outcomes in HF-CS.

Clinical presentation, shock severity and mortality in patients with de novo versus acute-on-chronic heart failure-related cardiogenic shock.

AIMS: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS. METHODS AND RESULTS: In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005). CONCLUSION: In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this.

Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock.

BACKGROUND: Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS. METHODS: Unselected, consecutive patients with CS and CRP measurements treated at a single large cardiovascular center between 2009 and 2019 were analyzed. Adjusted regression models were fitted to evaluate the association of CRP with shock severity, 30-day in-hospital mortality and treatment response to MCS. RESULTS: The analysis included 1116 patients [median age: 70 (IQR 58-79) years, 795 (71.3%) male, lactate 4.6 (IQR 2.2-9.5) mmol/l, CRP 17 (IQR 5-71) mg/l]. The cause of CS was acute myocardial infarction in 530 (48%) patients, 648 (58%) patients presented with cardiac arrest. Plasma CRP concentrations were equally distributed across shock severities (SCAI stage B-E). Higher CRP concentrations were associated with 30-day in-hospital mortality (8% relative risk increase per 50 mg/l increase in CRP, range 3-13%; p < 0.001), even after adjustment for CS severity and other potential confounders. Higher CRP concentrations were only associated with higher mortality in patients not treated with MCS [hazard ratio (HR) for CRP > median 1.50; 95%-CI 1.21-1.86; p < 0.001], but not in those treated with MCS (HR for CRP > median 0.92; 95%-CI 0.67-1.26; p = 0.59; p-interaction = 0.01). CONCLUSION: Elevated CRP concentrations are associated with increased 30-day in-hospital mortality in unselected patients with cardiogenic shock. The use of mechanical circulatory support attenuates this association.

Association between left ventricular ejection fraction, mortality and use of mechanical circulatory support in patients with non-ischaemic cardiogenic shock.

BACKGROUND: Currently, use of mechanical circulatory support (MCS) in non-ischaemic cardiogenic shock (CS) is predominantly guided by shock-specific markers, and not by markers of cardiac function. We hypothesise that left ventricular ejection fraction (LVEF) can identify patients with a higher likelihood to benefit from MCS and thus help to optimise their expected benefit. METHODS: Patients with non-ischaemic CS and available data on LVEF from 16 tertiary-care centres in five countries were analysed. Cox regression models were fitted to evaluate the association between LVEF and mortality, as well as the interaction between LVEF, MCS use and mortality. RESULTS: N = 807 patients were analysed: mean age 63 [interquartile range (IQR) 51.5-72.0] years, 601 (74.5%) male, lactate 4.9 (IQR 2.6-8.5) mmol/l, LVEF 20 (IQR 15-30) %. Lower LVEF was more frequent amongst patients with more severe CS, and MCS was more likely used in patients with lower LVEF. There was no association between LVEF and 30-day mortality risk in the overall study cohort. However, there was a significant interaction between MCS use and LVEF, indicating a lower 30-day mortality risk with MCS use in patients with LVEF ≤ 20% (hazard ratio 0.72, 95% confidence interval 0.51-1.02 for LVEF ≤ 20% vs. hazard ratio 1.31, 95% confidence interval 0.85-2.01 for LVEF > 20%, interaction-p = 0.017). CONCLUSION: This retrospective study may indicate a lower mortality risk with MCS use only in patients with severely reduced LVEF. This may propose the inclusion of LVEF as an adjunctive parameter for MCS decision-making in non-ischaemic CS, aiming to optimise the benefit-risk ratio.

Complications in patients with cardiogenic shock on veno-arterial extracorporeal membrane oxygenation therapy: distribution and relevance. Results from an international, multicentre cohort study.

AIMS: Veno-arterial extracorporeal membrane oxygenation therapy (VA-ECMO) restores circulation and tissue oxygenation in cardiogenic shock (CS) patients, but can also lead to complications. This study aimed to quantify VA-ECMO complications and analyse their association with overall survival as well as favourable neurological outcome (cerebral performance categories 1 + 2). METHODS AND RESULTS: All-comer patients with CS treated with VA-ECMO were retrospectively enrolled from 16 centres in four countries (2005-2019). Neurological, bleeding, and ischaemic adverse events (AEs) were considered. From these, typical VA-ECMO complications were identified and analysed separately as device-related complications. n = 501. Overall, 118 were women (24%), median age was 56.0 years, median lactate was 8.1 mmol/L. Acute myocardial infarction caused CS in 289 patients (58%). Thirty-days mortality was 40% (198/501 patients). At least one device-related complication occurred in 252/486 (52%) patients, neurological AEs in 108/469 (23%), bleeding in 192/480 (40%), ischaemic AEs in 123/478 (26%). The 22% of patients with the most AEs accounted for 50% of all AEs. All types of AEs were associated with a worse prognosis. Aside from neurological ones, all AEs and device-related complications were more likely to occur in women; although prediction of AEs outside of neurological AEs was generally poor. CONCLUSION: Therapy and device-related complications occur in half of all patients treated with VA-ECMO and are associated with a worse prognosis. They accumulate in some patients, especially in women. Aside from neurological events, identification of patients at risk is difficult, highlighting the need to establish additional quantitative markers of complication risk to guide VA-ECMO treatment in CS.

Incidence of hypoxic hepatitis in patients with cardiogenic shock and association with mortality.

AIMS: Shock of any cause leads to end-organ damage due to ischaemia, especially in perfusion-sensitive organs such as the liver. In septic shock, hypoxic hepatitis (S-HH) is defined as the 20-fold increase of the upper normal limit of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) and is associated with a mortality of up to 60%. However, as pathophysiology, dynamics, and treatment differ between septic and cardiogenic shock (CS), the S-HH definition may not be suitable for CS. Therefore, we aim to evaluate if the S-HH definition is applicable in CS patients. METHODS AND RESULTS: This analysis was based on a registry of all-comer CS patients treated between 2009 and 2019 at a tertiary care centre with exclusion of minors and patients without all necessary ASAT and ALAT values. N = 698. During in-hospital follow-up, 386 (55.3%) patients died. The S-HH was not significantly associated with in-hospital mortality in CS patients. To define HH among patients with CS (C-HH), optimal cut-off values were found to be ≥1.34-fold increase for ASAT and ≥1.51-fold increase for ALAT in serial measurements. The incidence of C-HH was 254/698 patients (36%) and C-HH showed a strong association with in-hospital mortality (odds ratio 2.36, 95% confidence interval: 1.61, 3.49). CONCLUSION: The C-HH is a frequent and relevant comorbidity in patients with CS, although its definition varies from the established definition of HH in patients with septic shock. As C-HH contributed to excess mortality risk, these findings emphasize the need for further investigation of therapies reducing the occurrence of C-HH and also improving the associated outcome.

Use of mechanical circulatory support in patients with non-ischaemic cardiogenic shock.

AIMS: Despite its high incidence and mortality risk, there is no evidence-based treatment for non-ischaemic cardiogenic shock (CS). The aim of this study was to evaluate the use of mechanical circulatory support (MCS) for non-ischaemic CS treatment. METHODS AND RESULTS: In this multicentre, international, retrospective study, data from 890 patients with non-ischaemic CS, defined as CS due to severe de-novo or acute-on-chronic heart failure with no need for urgent revascularization, treated with or without active MCS, were collected. The association between active MCS use and the primary endpoint of 30-day mortality was assessed in a 1:1 propensity-matched cohort. MCS was used in 386 (43%) patients. Patients treated with MCS presented with more severe CS (37% vs. 23% deteriorating CS, 30% vs. 25% in extremis CS) and had a lower left ventricular ejection fraction at baseline (21% vs. 25%). After matching, 267 patients treated with MCS were compared with 267 patients treated without MCS. In the matched cohort, MCS use was associated with a lower 30-day mortality (hazard ratio 0.76, 95% confidence interval 0.59-0.97). This finding was consistent through all tested subgroups except when CS severity was considered, indicating risk reduction especially in patients with deteriorating CS. However, complications occurred more frequently in patients with MCS; e.g. severe bleeding (16.5% vs. 6.4%) and access-site related ischaemia (6.7% vs. 0%). CONCLUSION: In patients with non-ischaemic CS, MCS use was associated with lower 30-day mortality as compared to medical therapy only, but also with more complications. Randomized trials are needed to validate these findings.

Timing of Active Left Ventricular Unloading in Patients on Venoarterial Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: It is currently unclear if active left ventricular (LV) unloading should be used as a primary treatment strategy or as a bailout in patients with cardiogenic shock (CS) treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO). OBJECTIVES: This study sought to evaluate the association between timing of active LV unloading and implantation of VA-ECMO with outcomes of patients with CS. METHODS: Data from 421 patients with CS treated with VA-ECMO and active LV unloading at 18 tertiary care centers in 4 countries were analyzed. Patients were stratified by timing of device implantation in early vs delayed active LV unloading (defined by implantation before up to 2 hours after VA-ECMO). Adjusted Cox and logistic regression models were fitted to evaluate the association between early active LV unloading and 30-day mortality as well as successful weaning from ventilation. RESULTS: Overall, 310 (73.6%) patients with CS were treated with early active LV unloading. Early active LV unloading was associated with a lower 30-day mortality risk (HR: 0.64; 95% CI: 0.46-0.88) and a higher likelihood of successful weaning from ventilation (OR: 2.17; 95% CI: 1.19-3.93) but not with more complications. Importantly, the relative mortality risk increased and the likelihood of successful weaning from ventilation decreased almost proportionally with the time interval between VA-ECMO implantation and (delayed) initiation of active LV unloading. CONCLUSIONS: This exploratory study lends support to the use of early active LV unloading in CS patients on VA-ECMO, although the findings need to be validated in a randomized controlled trial.

Early risk stratification in patients with cardiogenic shock irrespective of the underlying cause - the Cardiogenic Shock Score.

AIMS: Early risk stratification is essential to guide treatment in cardiogenic shock (CS). Existing CS risk scores were derived in selected cohorts, without accounting for the heterogeneity of CS. The aim of this study was to develop a universal risk score (the Cardiogenic Shock Score, CSS) for all CS patients, irrespective of the underlying cause. METHODS AND RESULTS: Within a registry of 1308 CS unselected patients admitted to a tertiary care hospital between 2009 and 2019, a Cox regression model was fitted to derive the CSS, with 30-day mortality as main outcome. The CSS's predictive ability was compared to the IABP-SHOCK II score, the CardShock score and SCAI classification by C-indices and validated in an external cohort of 934 CS patients. Based on the Cox regression, nine predictors were included in the CSS: age, sex, acute myocardial infarction (AMI-CS), systolic blood pressure, heart rate, pH, lactate, glucose and cardiac arrest. The CSS had the highest C-index in the overall cohort (0.740 vs. 0.677/0.683 for IABP-SHOCK II score/CardShock score), in patients with AMI-CS (0.738 vs. 0.675/0.689 for IABP-SHOCK II score/CardShock score) and in patients with non-AMI-CS (0.734 vs. 0.677/0.669 for IABP-SHOCK II score/CardShock score). In the external validation cohort, the CSS had a C-index of 0.73, which was higher than all other tested scores. CONCLUSION: The CSS provides improved information on the risk of death in unselected patients with CS compared to existing scores, irrespective of its cause. Because it is based on point-of-care variables which can be obtained even in critical situations, the CSS has the potential to guide treatment decisions in CS.

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

AIMS: Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCTs). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials. METHODS AND RESULTS: Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI, enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility. CONCLUSION: The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status.

Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing.

Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes Kif1b and Ddit3. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.