Blood Pressure and Oxygen Targets on Kidney Injury After Cardiac Arrest.

BACKGROUND: Acute kidney injury (AKI) represents a common and serious complication to out-of-hospital cardiac arrest. The importance of post-resuscitation care targets for blood pressure and oxygenation for the development of AKI is unknown. METHODS: This is a substudy of a randomized 2-by-2 factorial trial, in which 789 comatose adult patients who had out-of-hospital cardiac arrest with presumed cardiac cause and sustained return of spontaneous circulation were randomly assigned to a target mean arterial blood pressure of either 63 or 77 mm Hg. Patients were simultaneously randomly assigned to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa or a liberal oxygenation target of a Pao2 of 13 to 14 kPa. The primary outcome for this study was AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) classification in patients surviving at least 48 hours (N=759). Adjusted logistic regression was performed for patients allocated to high blood pressure and liberal oxygen target as reference. RESULTS: The main population characteristics at admission were: age, 64 (54-73) years; 80% male; 90% shockable rhythm; and time to return of spontaneous circulation, 18 (12-26) minutes. Patients allocated to a low blood pressure and liberal oxygen target had an increased risk of developing AKI compared with patients with high blood pressure and liberal oxygen target (84/193 [44%] versus 56/187 [30%]; adjusted odds ratio, 1.87 [95% CI, 1.21-2.89]). Multinomial logistic regression revealed that the increased risk of AKI was only related to mild-stage AKI (KDIGO stage 1). There was no difference in risk of AKI in the other groups. Plasma creatinine remained high during hospitalization in the low blood pressure and liberal oxygen target group but did not differ between groups at 6- and 12-month follow-up. CONCLUSIONS: In comatose patients who had been resuscitated after out-of-hospital cardiac arrest, patients allocated to a combination of a low mean arterial blood pressure and a liberal oxygen target had a significantly increased risk of mild-stage AKI. No difference was found in terms of more severe AKI stages or other kidney-related adverse outcomes, and creatinine had normalized at 1 year after discharge. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099.

Accelerometer-measured physical activity in patients with heart failure and reduced ejection fraction: Determinants and relationship with patient-reported health status.

BACKGROUND: Accelerometer-measured physical activity is an increasingly used endpoint in heart failure (HF) trials. We investigated the determinants of accelerometer-measured physical activity and the relationship with patient-reported health status. METHODS: Post-hoc analysis of the Empire HF trial, including outpatients with HF with reduced ejection fraction (HFrEF). Physical activity was quantified as average accelerometer counts per minute (CPM) with higher values representing higher activity. We investigated associations between activity level and clinical variables, including age, sex, and body mass index, as well as patient-reported health status assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ). RESULTS: Complete data were available in 180 (95%) patients (86% male, mean age 65 year). Baseline median physical activity level was 1,318 CPM (Q1-Q3 1,111-1,585). Age and anemia were independently associated with activity level (ß-coefficients: -10 CPM per year age increase [95% CI -16 to -5.1], P = .00015, and -126 CPM for anemia [95% CI -9.1 to -244], P = .035). Significant independent associations were observed between activity level and all KCCQ summary scores (ß-coefficient point estimates of 3.7, 4.6, and 4.9 CPM, all P < .02). For 12-week changes in KCCQ-summary scores, only the KCCQ-CSS was associated with activity level; mean increase of 17.5 CPM [95% CI 1.5 to 34.0], P = 0.032, per 5-point increase in KCCQ-CSS. Associations were not modified by treatment allocation (interaction P-values > .05). CONCLUSIONS: In patients with HFrEF, older age and anemia were independently associated with lower activity. Moreover, physical activity only weakly increased with better health status, suggesting that changes in physical activity reflect improvements in patients' health status to a limited degree. This highlights the need to better understand the endpoint with regards to all other health parameters to ease interpretation in future HF trials.

NatIonal Danish endocarditis stUdieS - Design and objectives of the NIDUS registry.

AIMS: The NatIonal Danish endocarditis stUdieS (NIDUS) registry aims to investigate the mechanisms contributing to the increasing incidence of infective endocarditis (IE) and to discover risk factors associated to the course, treatment and clinical outcomes of the disease. METHODS: The NIDUS registry was created to investigate a nationwide unselected group of patients hospitalized for IE. The National Danish healthcare registries have been queried for validated IE diagnosis codes (International Classification of Disease, 10th edition [ICD-10]: DI33, DI38, and DI398). Subsequently, a team of 28 healthcare professionals, including experts in endocarditis, will systematically review and evaluate all identified patient records using the modified Duke Criteria and the 2015 European Society of Cardiology modified diagnostic criteria. The registry will contain all cases with definite or possible IE found in primary data sources in Denmark between January 1, 2016, and December 31, 2021. We will gather individual patient data, such as clinical, microbiological, and echocardiographic characteristics, treatment regimens, and clinical outcomes. A digital data collection form will be used to the gathering of data. A sample of approximately 4,300 individual patients will be evaluated using primary data sources. CONCLUSIONS AND PERSPECTIVES: The NIDUS registry will be the first comprehensive nationwide IE registry, contributing critical knowledge about the course, treatment, and clinical outcomes of the disease. Additionally, it will significantly aid in identifying areas in which future research is needed.

Empagliflozin to elderly and obese patients with increased risk of developing heart failure: Study protocol for the Empire Prevent trial program.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF. METHODS: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m2) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up. DISCUSSION: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition. TRIAL REGISTRATION: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome.

Future for cardiogenic shock research.

PURPOSE OF REVIEW: To discuss future research themes and study design in cardiogenic shock. RECENT FINDINGS: Cardiogenic shock research faces multiple challenges, hindering progress in understanding and treating this life-threatening condition. Cardiogenic shock's heterogeneous nature poses challenges in patient selection for clinical trials, potentially leading to variability in treatment responses and outcomes. Ethical considerations arise due to the acuity and severity of the condition, posing challenges in obtaining informed consent and conducting randomized controlled trials where time to treatment is pivotal. SUMMARY: This review discusses research in this area focusing on the importance of phenotyping patients with cardiogenic shock, based on artificial intelligence, machine learning, and unravel new molecular mechanisms using proteomics and metabolomics. Further, the future research focus in mechanical circulatory support and targeting inflammation is reviewed. Finally, newer trial designs including adaptive platform trials are discussed.

First-In-Man Trial of ß3-Adrenoceptor Agonist Treatment in Chronic Heart Failure: Impact on Diastolic Function.

ABSTRACT: Diastolic dysfunction (DD) in heart failure is associated with increased myocardial cytosolic calcium and calcium-efflux through the sodium-calcium exchanger depends on the sodium gradient. Beta-3-adrenoceptor (ß3-AR) agonists lower cytosolic sodium and have reversed organ congestion. Accordingly, ß3-AR agonists might improve diastolic function, which we aimed to assess. In a first-in-man, randomized, double-blinded trial, we assigned 70 patients with HF with reduced ejection fraction, New York Heart Association II-III, and left ventricular ejection fraction <40% to receive the ß3-AR agonist mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended heart failure therapy. We performed echocardiography and cardiac computed tomography and measured N-terminal probrain natriuretic peptide at baseline and follow-up. DD was graded per multiple renowned algorithms. Baseline and follow-up data were available in 57 patients (59 ± 11 years, 88% male, 49% ischemic heart disease). No clinically significant changes in diastolic measurements were found within or between the groups by echocardiography (E/e' placebo: 13 ± 7 to 13 ± 5, P = 0.21 vs. mirabegron: 12 ± 6 to 13 ± 8, P = 0.74, between-group follow-up difference 0.2 [95% CI, -3 to 4], P = 0.89) or cardiac computed tomography (left atrial volume index: between-group follow-up difference 9 mL/m 2 [95% CI, -3 to 19], P = 0.15). DD gradings did not change within or between the groups following 2 algorithms ( P = 0.72, P = 0.75). N-terminal probrain natriuretic peptide remained unchanged in both the groups ( P = 0.74, P = 0.64). In patients with HF with reduced ejection fraction, no changes were identified in diastolic measurements, gradings or biomarker after ß3-AR stimulation compared with placebo. The findings add to the previous literature questioning the role of impaired Na + -Ca 2+ -mediated calcium export as a major culprit in DD. NCT01876433.

Acute kidney injury after out-of-hospital cardiac arrest.

BACKGROUND: Acute kidney injury (AKI) is a significant risk factor associated with reduced survival following out-of-hospital cardiac arrest (OHCA). Whether the severity of AKI simply serves as a surrogate measure of worse peri-arrest conditions, or represents an additional risk to long-term survival remains unclear. METHODS: This is a sub-study derived from a randomized trial in which 789 comatose adult OHCA patients with presumed cardiac cause and sustained return of spontaneous circulation (ROSC) were enrolled. Patients without prior dialysis dependent kidney disease and surviving at least 48 h were included (N = 759). AKI was defined by the kidney disease: improving global outcome (KDIGO) classification, and patients were divided into groups based on the development of AKI and the need for continuous kidney replacement therapy (CKRT), thus establishing three groups of patients-No AKI, AKI no CKRT, and AKI CKRT. Primary outcome was overall survival within 365 days after OHCA according to AKI group. Adjusted Cox proportional hazard models were used to assess overall survival within 365 days according to the three groups. RESULTS: In the whole population, median age was 64 (54-73) years, 80% male, 90% of patients presented with shockable rhythm, and time to ROSC was median 18 (12-26) min. A total of 254 (33.5%) patients developed AKI according to the KDIGO definition, with 77 requiring CKRT and 177 without need for CKRT. AKI CKRT patients had longer time-to-ROSC and worse metabolic derangement at hospital admission. Overall survival within 365 days from OHCA decreased with the severity of kidney injury. Adjusted Cox regression analysis found that AKI, both with and without CKRT, was significantly associated with reduced overall survival up until 365 days, with comparable hazard ratios relative to no AKI (HR 1.75, 95% CI 1.13-2.70 vs. HR 1.76, 95% CI 1.30-2.39). CONCLUSIONS: In comatose patients who had been resuscitated after OHCA, patients developing AKI, with or without initiation of CKRT, had a worse 1-year overall survival compared to non-AKI patients. This association remains statistically significant after adjusting for other peri-arrest risk factors. TRIAL REGISTRATION: The BOX trial is registered at ClinicalTrials.gov: NCT03141099.

Danish-German cardiogenic shock trial-DanGer shock: Trial design update.

BACKGROUND: The main objective of the Danish German Cardiogenic Shock trial (DanGer Shock ClinicalTrials.gov Identifier: NCT01633502) is to assess the efficacy of the trans valvular axial flow device Impella CP in treating patients with AMICS shock due to STEMI undergoing emergency percutaneous coronary intervention. METHODS: This statistical analysis plan represents an overview of the statistical methods which will be used for analyzing the DanGer Shock trial. RESULTS: The primary study endpoint is death from all causes through 180 days in the intention to treat population (all randomized consented patients). The secondary endpoints comprise; composite event of the need for additional mechanical support, need for cardiac transplantation, and death of all causes whichever comes first; and days alive and out of hospital. As exploratory analyses an as treated analysis of primary endpoint will be performed. Composite safety endpoint will comprise of major bleeding, vascular complications, device malfunction, damage to the aortic valve, and significant hemolysis. The primary endpoint death rate at 180 days will be analyzed using Cox proportional hazards analysis. The result will be reported as hazard ratio and corresponding 95% confidence interval (95% CI). No imputation of missing values will be performed. Additional statistical analyses for predefined hemodynamic, metabolic, renal, hematological, and health economics substudies will be specified in separate protocols. CONCLUSION: Main analyses of the primary and secondary outcomes of the DanGer Shock trial will be conducted according to this publication.

Importance of familial predisposition to heart failure to the risk of anthracycline-related cardiotoxicity: A nationwide study.

BACKGROUND: Anthracycline-based chemotherapy has improved the prognosis of various malignancies, but increases the long-term risk of heart failure (HF). Identification of patients at risk prior to treatment initiation is warranted. Therefore, the aim of this study was to evaluate if a familial predisposition to HF increases the risk of anthracycline related HF. METHODS: Using nationwide Danish registries, all patients treated with anthracycline from 2004 to 16 were identified. The primary outcome was long-term HF risk. First-degree relatives were identified in the Danish Family Registry and exposure was defined as a first-degree biological relative with prior HF. Risk of HF was evaluated in a cumulative incidence function and the association in a multivariable Cox regression model. RESULTS: A total of 11,651 patients (median age 49.1 years (IQR: 43.6-53.7), 12.2% male) were included after exclusion of 46 with preanthracycline HF. Median follow-up was 3.8 years (IQR 1.9-6.4). In the group with a first-degree relative with HF (n = 1,608) 35 patients (2.2%) were diagnosed with HF vs 133 (1.3%) in the group without a first-degree relative with HF (n = 10,043), corresponding to incidence rates per 1,000 patient-years of 5.2 (CI:3.8-7.3) vs 3.0 (CI:2.5-3.5). The cumulative incidence of HF after 10 years was higher in the first-degree relative group (3.2% vs 2.0%, P = .004); adjusted hazard ratio 1.53 (CI:1.05-2.23, P = .03). CONCLUSION: In this nationwide register-based study having a first-degree relative with HF was associated with increased risk of anthracycline related HF, suggesting that attention towards family predisposition may be warranted when estimating the risk of anthracycline related cardiotoxicity.

Glimpse into the future.

Randomized studies attempting to prove benefit of mechanical circulatory support in cardiogenic shock have failed to reduce the risk of death. Further, both registry and randomized data suggest increased rates of serious complications associated with these devices. This last review in the supplement discusses current evidence and provides a perspective on how the scientific community could advance cardiogenic shock research focused on mechanical circulatory support.

Timing and treatment strategies according to SCAI classification in cardiogenic shock.

In patients with cardiogenic shock (CS), particularly those with acute myocardial infarction (AMI), evidence suggests that timely diagnosis and treatment interventions are critical in the prevention of haemo-metabolic compromise. Temporary mechanical circulatory support (tMCS) has shown potential in facilitating revascularization and recovery of patients with acute myocardial infarction cardiogenic shock (AMI-CS). Timing of treatment strategies for CS patients needs to be optimized for use of tMCS devices that are applicable to this heterogeneous patient population. Here, the latest evidence as well as the gaps in knowledge surrounding the role of time in the management of patients with CS is summarized.

Monitoring MCS patients on the intensive care unit: integrating haemodynamic assessment, laboratory data, and imaging techniques for timely detection of deterioration and recovery.

Monitoring of the patient supported with a temporary mechanical circulatory support (tMCS) is crucial in achieving the best possible outcome. Monitoring is a continuous and labour-intensive process, as cardiogenic shock (CS) patients can rapidly deteriorate and may require new interventions within a short time period. Echocardiography and invasive haemodynamic monitoring form the cornerstone of successful tMCS support. During monitoring, it is particularly important to ensure that adequate end-organ perfusion is achieved and maintained. Here, we provide a comprehensive overview of best practices for monitoring the CS patient supported by a micro-axial flow pump, veno-arterial extracorporeal membrane oxygenation, and both devices simultaneously (ECMELLA approach). It is a complex process that encompasses device control, haemodynamic control and stabilization, monitoring of interventions, and assessment of end-organ function. The combined, continuous, and preferably protocol-based approach of echocardiography, evaluation of biomarkers, end-organ assessment, and haemodynamic parameters is crucial in assessing this critically ill CS patient population.

Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial.

BACKGROUND: Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury. METHODS: Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis. RESULTS: The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P<0.001. There were no differences in survival or neurological outcome. CONCLUSIONS: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.

Diagnostic accuracy of focused deep venous, lung, cardiac and multiorgan ultrasound in suspected pulmonary embolism: a systematic review and meta-analysis.

OBJECTIVE: To determine the diagnostic accuracy of point-of-care ultrasound in suspected pulmonary embolism. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, CINAHL and Cochrane library were searched on 2 July 2020 with no restrictions on the date of publication. Subject headings or subheadings combined with text words for the concepts of pulmonary embolism, ultrasound and diagnosis were used. ELIGIBILITY CRITERIA AND DATA ANALYSIS: Eligible studies reported sensitivity and specificity of deep venous, lung, cardiac or multiorgan ultrasound in patients with suspected pulmonary embolism, using an adequate reference-test. Prospective, cross-sectional and retrospective studies were considered for eligibility. No restrictions were made on language. Studies were excluded if a control group consisted of healthy volunteers or if transesophageal or endobronchial ultrasound was used. Risk of bias was assessed using quality assessment of diagnostic accuracy studies-2. Meta-analysis of sensitivity and specificity was performed by construction of hierarchical summary receiver operator curves. I2 was used to assess the study heterogeneity. MAIN OUTCOME MEASURES: The primary outcome was overall sensitivity and specificity of reported ultrasound signs, stratified by organ approach (deep venous, lung, cardiac and multiorgan). Secondary outcomes were stratum-specific sensitivity and specificity within subgroups defined by pretest probability of pulmonary embolism. RESULTS: 6378 references were identified, and 70 studies included. The study population comprised 9664 patients with a prevalence of pulmonary embolism of 39.9% (3852/9664). Risk of bias in at least one domain was found in 98.6% (69/70) of included studies. Most frequently, 72.8% (51/70) of studies reported >24 hours between ultrasound examination and reference test or did not disclose time interval at all. Level of heterogeneity ranged from 0% to 100%. Most notable ultrasound signs were bilateral compression of femoral and popliteal veins (22 studies; 4708 patients; sensitivity 43.7% (36.3% to 51.4%); specificity 96.7% (95.4% to 97.6%)), presence of at least one hypoechoic pleural-based lesion (19 studies; 2134 patients; sensitivity 81.4% (73.2% to 87.5%); specificity 87.4% (80.9% to 91.9%)), D-sign (13 studies; 1579 patients; sensitivity 29.7% (24.6% to 35.4%); specificity 96.2% (93.1% to 98.0%)), visible right ventricular thrombus (5 studies; 995 patients; sensitivity 4.7% (2.7% to 8.1%); specificity 100% (99.0% to 100%)) and McConnell's sign (11 studies; 1480 patients; sensitivity 29.1% (20.0% to 40.1%); specificity 98.6% (96.7% to 99.4%)). CONCLUSION: Several ultrasound signs exhibit a high specificity for pulmonary embolism, suggesting that implementation of ultrasound in the initial assessment of patients with suspected pulmonary embolism may improve the selection of patients for radiation imaging. PROSPERO REGISTRATION NUMBER: CRD42020184313.

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.

The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker).

BACKGROUND: Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients. METHODS: This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed. RESULTS: A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918-1720) pg/mL with empagliflozin, and 1299 (952-1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03-1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = - 0.23, p = 0.031), and end-diastolic volume (R = - 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86-1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97-1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01. CONCLUSION: Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP. TRIAL REGISTRATION: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.

Association between inflammatory markers and survival in comatose, resuscitated out-of-hospital cardiac arrest patients.

OBJECTIVES: Prognostication after out-of-hospital cardiac arrest (OHCA) remains challenging. The inflammatory response after OHCA has been associated with increased mortality. This study investigates the associations and predictive value between inflammatory markers and outcome in resuscitated OHCA patients. DESIGN: The study is based on post hoc analyses of a double-blind controlled trial, where resuscitated OHCA patients were randomized to receive either exenatide or placebo. Blood was analyzed for levels of inflammatory markers the day following admission. Primary endpoint was time to death for up to 180 days. Secondary endpoints included 180-day mortality and poor neurological outcome after 180 days, defined as a cerebral performance category (CPC) of 3 to 5. RESULTS: Among 110 included patients we found significant associations between higher leucocyte quartile and increasing mortality in univariable analysis (OR 2.6 (95%CI 1.6-4.2), p < .001), as well as in multivariable analysis (OR 2.1 (95%CI 1.1-4.0), p = .02). A significant association was found between higher neutrophil quartile and increasing mortality in univariable analysis (OR 3.0 (95%CI 1.8-5.0), p < .001) as well as multivariable analysis (OR 2.4 (95%CI 1.2-4.6), p = .01). Leucocyte and neutrophil levels were predictive of poor outcome after 180 days with area under the receiver operating characteristics curves of 0.79 and 0.81, respectively. We found no associations between CRP and lymphocyte levels versus outcome. CONCLUSIONS: Total leucocyte count and neutrophil levels measured the first day following OHCA were significantly associated with 180-day all-cause mortality and may potentially act as early predictors of outcome. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, unique identifier: NCT02442791.

Vasodilators for acute heart failure-A protocol for a systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis.

BACKGROUND: Above one million annual hospitalizations occur with a primary diagnosis of acute heart failure in the US, with comparable numbers in Europe. Within 1 year, over a third of patients have died or been re-hospitalized. Most patients have acutely elevated systemic and/or intra-cardiac blood pressures as part of the acute heart failure syndrome. Most clinical trials of acute heart failure have aimed at reducing preload and/or afterload through drug-induced vasodilation. However, recent European guidelines downgraded the treatment recommendation of vasodilators. We aim to assess the beneficial and harmful effects of vasodilators in the treatment of acute heart failure. METHODS: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We plan to include all randomized clinical trials assessing the use of vasodilators in the treatment of AHF. The systematic review will be conducted based on a systematic search of relevant major medical databases without date restrictions, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) in addition to clinical trial registries. We will begin the searches in August 2022. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our conclusions will be based on the results from the primary outcomes with concomitant low risk of bias. Extracted data will be analyzed using Trial Sequential Analysis 0.9.5.10, Review Manager 5.3, and SAS. We will assess the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation. We will register this systematic review at Prospero and aim to update it when new trials are published. DISCUSSION: This protocol defines the detailed methodology and approach used for a systematic review on whether vasodilation for acute heart failure improves patient outcome. This systematic review will potentially aid clinicians in deciding the optimal treatment of patients admitted with acute heart failure. Furthermore, this review will explore gaps in our knowledge and thus guide future research within acute heart failure.

Admission biomarkers among patients with acute myocardial-infarction related cardiogenic shock with or without out-of-hospital cardiac arrest an exploratory study.

BACKGROUND: Acute myocardial infarction complicated by cardiogenic shock (AMICS) with or without out-of-hospital cardiac arrest (OHCA) have some pathophysiological differences and could potentially be considered as two individual clinical entities. Thus, there may also be differences in terms of blood borne biomarkers. PURPOSE: To explore potential differences in concentrations of the biomarkers lactate, mid-regional proadrenomedullin (MRproADM), Copeptin, pro-atrial natriuretic peptide (proANP), Syndecan-1, soluble thrombomodulin (sTM), soluble suppression of tumorigenicity 2 (sST2) and neutrophil gelatinase-associated lipocalin (NGAL), in patients with AMICS with or without OHCA. METHOD: Patients admitted for acute coronary angiography due to suspected ST-elevation myocardial infarction were enrolled during a 1-year period. In the present study 86 patients with confirmed AMICS at admission were included. RESULTS: In the adjusted analysis OHCA patients had higher levels of lactate (p = 0.008), NGAL (p = 0.03) and sTM (p = 0.011) while the level of sST2 was lower (p = 0.029). There was little difference in 30-day mortality between the OHCA and non-OHCA groups (OHCA 37% vs. non-OHCA 38%). CONCLUSION: AMICS patients with or without OHCA had similar 30-day mortality but differed in terms of Lactate, NGAL, sTM and sST2 levels. These findings support that non-OHCA and OHCA patients with CS could be considered as two individual clinical entities.

Association of Body Mass Index with Mortality in Patients with Cardiogenic Shock following Acute Myocardial Infarction: A Contemporary Danish Cohort Analysis.

AIMS: The obesity paradox suggests a better prognosis in overweight or obese patients with heart failure and acute myocardial infarction (AMI) than patients with normal weight. Few studies have investigated the association between BMI and mortality in patients with AMI complicated by cardiogenic shock (AMICS). The aim of this study was to evaluate the association between BMI and 30-day mortality in patients with AMICS. METHODS AND RESULTS: A retrospective study of 1,716 patients with AMICS treated at 2 tertiary centers in south-eastern Denmark between 2010 and 2017. Patients undergoing revascularization and who were admitted to the intensive care unit were included (n = 1,216). BMI was available in 1,017 patients (83.6%). Patients were divided according to the WHO classification as normal weight BMI <24.9 kg/m2 (n = 453), overweight BMI 25-29.9 kg/m2 (n = 391), obese class 1 BMI 30-34.9 kg/m2 (n = 131), and obese class 2 + 3 BMI >35 kg/m2 (n = 42). Differences in baseline characteristics, in-hospital treatment, and the primary outcome of all-cause mortality at 30 days were examined. Obese patients had more comorbidities such as diabetes, hypertension, and dyslipidemia than patients with normal weight. Need for renal replacement therapy was higher among obese patients (normal weight, 19% vs. obese class 2 + 3, 35%, p = 0.02); otherwise, no difference in management was found. No difference in 30-day mortality was observed between groups (normal weight 44%, overweight 38%, obese class 1 41%, and obese class 2 + 3 45% at 30 days; ns). CONCLUSIONS: Thirty-day mortality in patients with AMICS was not associated with the BMI category. Thus, evidence of an "obesity paradox" was not observed in this contemporary cohort of patients with AMICS in Denmark.