Unloading in cardiogenic shock: the rationale and current evidence.

PURPOSE OF REVIEW: Discussing the rationale and current evidence for left ventricular unloading in cardiogenic shock. RECENT FINDINGS: Microaxial flow pumps (MFP) and intra-aortic balloon pumps (IABP) augment cardiac output while simultaneously unloading the left ventricle (e.g. reducing left ventricular pressure), thereby targeting a key mechanism of cardiogenic shock. A recent randomized trial has shown a mortality reduction with MFP in selected patients with cardiogenic shock, strengthening the rationale for this strategy, although the evidence for the IABP is so far neutral. MFP/IABP can also be used concomitantly with veno-arterial extracorporeal membrane oxygenation (va-ECMO) to alleviate the va-ECMO-related increase in left ventricular afterload, to facilitate weaning and ultimately to improve myocardial recovery and prognosis of affected patients. However, the use of MFP/IABP in this indication solely relies on retrospective data, which need to be interpreted with caution, especially as these strategies are associated with more complications. Currently ongoing randomized trials will help to further clarify the role of left ventricular unloading in patients on va-ECMO. SUMMARY: Left ventricular unloading addresses a key mechanism of cardiogenic shock, with strong evidence to support MFP use in selected patients, but further randomized controlled trials are required to clarify the role of different devices/strategies for the overall shock population.

Pro-adrenomedullin associates with congestion in acute heart failure patients.

AIM: Congestion is a major determinant of outcomes in acute heart failure. Its assessment is complex, making sufficient decongestive therapy a challenge. Residual congestion is frequent at discharge, increasing the risk of re-hospitalization and death. Mid-regional pro-adrenomedullin mirrors vascular integrity and may therefore be an objective marker to quantify congestion and to guide decongestive therapies in patients with acute heart failure. METHODS AND RESULTS: Observational, prospective, single-centre study in unselected patients presenting with acute heart failure. This study aimed to assess adrenomedullin's association with congestion and clinical outcomes: in-hospital death, post-discharge mortality and in-hospital worsening heart failure according to RELAX-AHF-2 trial criteria. Pro-adrenomedullin was quantified at baseline and at discharge. Congestion was assessed applying clinical scores. Cox and logistic regression models with adjustment for clinical features were fitted. N = 233, median age 77 years (IQR 67, 83), 148 male (63.5%). Median pro-adrenomedullin 2.0 nmol/L (IQR 1.4, 2.9). Eight patients (3.5%) died in hospital and 100 (44.1%) experienced in-hospital worsening heart failure. After discharge, 60 patients (36.6%) died over a median follow-up of 1.92 years (95% CI: 1.76, 2.46). Pro-adrenomedullin concentrations (logarithmized) were significantly associated with congestion, both at enrolment (ß = 0.36 and 0.81 depending on score, each P < 0.05) and at discharge (ß = 1.12, P < 0.001). Enrolment of pro-adrenomedullin was associated with in-hospital worsening heart failure [OR 4.23 (95% CI: 1.87, 9.58), P < 0.001], and pro-adrenomedullin at discharge was associated with post-discharge death [HR 3.93 (1.86, 8.67), P < 0.001]. CONCLUSION: Elevated pro-adrenomedullin is associated with in-hospital worsening heart failure and with death during follow-up in patients with acute heart failure. Further research is needed to validate this finding and to explore the ability of pro-adrenomedullin to guide decongestive treatment.

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.

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.

Timing of veno-arterial extracorporeal membrane oxygenation support in patients with cardiogenic shock.

AIMS: The optimal timing for implementing mechanical circulatory support (MCS) in cardiogenic shock (CS) remains indeterminate. This study aims to evaluate patient characteristics and outcome associated with the time interval between CS onset and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) implementation. METHODS AND RESULTS: In this study, patients with CS treated with MCS at 15 tertiary care centres in three countries were enrolled. Patients treated with MCS were stratified into early (<2 h), intermediate (2-12 h) and delayed (≥12-24 h) MCS implantation by using the time interval between CS onset and MCS device implementation. Adjusted logistic and Cox regression models were fitted to assess the association between timing of MCS implementation, patient characteristics and 30-day mortality. A total of 330 patients with CS treated with VA-ECMO and/or microaxial flow pump were included in this study; 20.9% received early, 55.8% intermediate, and 23.3% delayed MCS. Although crude 30-day mortality was slightly lower in patients with early MCS (58.1% vs. 64.7% vs. 64.3%), adjusted analyses showed no significant association between timing of MCS implantation and 30-day all-cause mortality (hazard ratio [HR] for early vs. intermediate MCS: 0.93, 95% confidence interval [CI] 0.59-1.46, p = 0.74; HR for early vs. delayed MCS: 1.29, 95% CI 0.78-2.13, p = 0.33). Moreover, the incidence of complications, related and unrelated to MCS, did not differ significantly among groups. CONCLUSION: In this exploratory study of patients with CS treated with MCS, the timing of device implantation within 24 h after CS onset was not associated with mortality. This supports a restrictive MCS approach, reserving its application for patients experiencing CS deterioration despite conventional therapy.

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.

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 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.

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.

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.

Coronary magnetic resonance imaging after routine implantation of bioresorbable vascular scaffolds allows non-invasive evaluation of vascular patency.

BACKGROUND: Evaluation of recurrent angina after percutaneous coronary interventions is challenging. Since bioresorbable vascular scaffolds (BVS) cause no artefacts in magnetic resonance imaging (MRI) due to their polylactate-based backbone, evaluation of vascular patency by MRI might allow for non-invasive assessment and triage of patients with suspected BVS failure. METHODS: Patients with polylactate-based ABSORB-BVS in proximal coronary segments were examined with 3 Tesla MRI directly (baseline) and one year after implantation. For assessment of coronary patency, a high-resolution 3D spoiled gradient echo pulse sequence with fat-saturation, T2-preparation (TE: 40 ms), respiratory and end-diastolic cardiac gating, and a spatial resolution of (1.08 mm)3 was positioned parallel to the course of the vessel for bright blood imaging. In addition, a 3D navigator-gated T2-weighted variable flip angle turbo spin echo (TSE) sequence with dual-inversion recovery black-blood preparation and elliptical k-space coverage was applied with a voxel size of (1.14 mm)3. For quantitative evaluation lumen diameters of the scaffolded areas were measured in reformatted bright and black blood MR angiography data. RESULTS: 11 patients with implantation of 16 BVS in the proximal coronary segments were included, of which none suffered from major adverse cardiac events during the one year follow up. Vascular patency in all segments implanted with BVS could be reliably assessed by MRI at baseline and after one year, whereas segments with metal stents could not be evaluated due to artefacts. Luminal diameter within the BVS remained constant during the one year period. One patient with atypical angina after BVS implantation was noninvasively evaluated showing a patent vessel, also confirmed by coronary angiography. CONCLUSIONS: Coronary MRI allows contrast-agent free and non-invasive assessment of vascular patency after ABSORB-BVS implantation. This approach might be supportive in the triage and improvement of diagnostic workflows in patients with postinterventional angina and scaffold implantation. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00007456.