Lower ST-elevation myocardial infarction incidence during COVID-19 epidemic in Northern Europe.

We compared the ST elevation myocardial infarction (STEMI) incidence during COVID-19 pandemic (March 2020) to January-February 2020 and to same time period in earlier years 2017-2019 in five Nordic-Baltic tertiary centers. During 2017-2019, there were no marked differences in STEMI incidence between January, February and March. During 2020, there was an average drop of 32% in STEMI incidence in March. The isolation measures may decrease the risk for respiratory virus infection and contribute to the lower STEMI incidence and that we might benefit from firmer suggestions on hand hygiene and social distancing during flu season at least among high-risk individuals.

Microvascular perfusion in infarcted and remote myocardium after successful primary PCI: angiographic and CMR findings.

OBJECTIVES: The aim of this study was to investigate the association between TIMI myocardial perfusion (TMP) grading acute and cardiac magnetic resonance (CMR) first-pass perfusion early and at 4 months in patients with ST-segment-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI). MATERIAL AND METHODS: One hundred ninety-eight STEMI patients were recruited from the POSTEMI study. TMP grade was assessed after PCI; CMR was performed at day 2 and after 4 months. Signal intensity was measured on first-pass perfusion images, and a maximum contrast enhancement index (MCE) was calculated. RESULTS: Patients with TMP grade 2-3 (n = 108) after PCI had significantly better EF (59 ± 10 vs. 51 ± 13, p < 0.001) and smaller infarct volume (12 ± 8 vs. 19 ± 12 %, p < 0.001) at 4 months compared with patients with TMP grade 0-1 (n = 81). MCE in the infarcted (MCEi) and remote myocardium (MCEr) improved from early to follow-up CMR, MCEi from 94 ± 56 to 126 ± 59, p < 0.001, and MCEr from 112 ± 51 to 127 ± 50, p < 0.001. In patients with the lowest CMR perfusion early, perfusion at 4 months remained decreased compared with the other groups, MCEi 108 ± 75 vs. 133 ± 51, p = 0.01, and MCEr 115 ± 41 vs. 131 ± 52, p = 0.047. CONCLUSION: TMP grade and early CMR first-pass perfusion were associated with CMR outcomes at 4 months. First-pass perfusion improved after 4 months in the infarcted and remote myocardium. However, in patients with the lowest CMR perfusion early, perfusion was still reduced after 4 months. KEY POINTS: • Cardiac magnetic resonance myocardial first-pass perfusion and TMP grading after successful PCI helps to assess risk in patients with ST elevation myocardial infarction. • Cardiac magnetic resonance myocardial first-pass perfusion shows that microvascular perfusion after ST elevation myocardial infarction can be impaired in both infarcted and non-infarcted myocardium. • Microvascular perfusion improves over time in patients with ST elevation myocardial infarction treated with primary PCI.

Long-Term Survival after Invasive or Conservative Strategy in Elderly Patients with non-ST-Elevation Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: The optimal management of elderly patients with non-ST-segment elevation myocardial infarction (NSTEMI) is still discussed. We aimed to study short- and long-term survival in NSTEMI patients ≥75 years managed with an invasive or a conservative strategy. METHODS: NSTEMI patients admitted to Oslo University Hospital Ulleval during 2005-2011 were included consecutively in a prospective registry. Vital status until December 31, 2013, was obtained from the Norwegian Cause of Death Registry. Patients ≥75 years were identified, and 30-day and 7-year survival were analyzed. Logistic- and Cox regression was used to estimate OR and hazard ratio (HR) for death in the invasive versus conservative group, adjusting for registered confounders. RESULTS: There were 2,064 NSTEMI patients ≥75 years (48.2% women); 1,200 (58.1%) were treated with an invasive strategy, and were younger, more likely to be male and previously revascularized compared to 864 (41.9%) patients treated conservatively (p < 0.0001 for all). Survival at 30-day was 94.9% in the invasive and 76.6% in the conservative group. For 30-day survivors, 7-year survival was 47.4% (95% CI 42.9-51.8) and 11.6% (95% CI 8.3-15.6), respectively. After multivariate adjustment, an invasive strategy was associated with lower long-term risk (adjusted HR [aHR] 0.49 [95% CI 0.41-0.59]). Actual revascularization was associated with lower risk of long-term mortality compared to angiography only (aHRPCI 0.73 [95% CI 0.59-0.90], aHRCABG 0.43 [95% CI 0.28-0.65]). CONCLUSION: In this real-life cohort of NSTEMI patients ≥75 years, 30-day survival was 95%, and 7-year survival was 47% with an invasive strategy. Revascularized patients had a superior long-term prognosis. With a conservative strategy, short- and long-term survival was lower, probably due to selection bias and unmeasured confounding.

Glucose associated NETosis in patients with ST-elevation myocardial infarction: an observational study.

BACKGROUND: Neutrophil extracellular traps (NETs) have recently been identified as mediators in atherothrombosis. Although NETosis in general has been suggested to be glucose dependent, the transferability to patients with acute ST-elevation myocardial infarction (STEMI) is unclear. We assessed whether the NETs markers double-stranded deoxyribonucleid acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) associated with plasma glucose and the glucometabolic status in the acute phase and 3 months after a STEMI. We also explored whether an acute glucose load resulted in upregulated NETosis by assessment of peptidylarginine deiminase 4 (PAD4) gene expression. METHODS: In total, 224 STEMI patients were prospectively enrolled and underwent blood sampling acutely (median 16.5 h after PCI) and after 3 months. Glucometabolic status was defined based on the results of an oral glucose tolerance test (OGTT) as normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or type 2 diabetes (T2DM). dsDNA and MPO-DNA were measured in serum, while PAD4 mRNA was measured in circulating leukocytes by RT-PCR. RESULTS: dsDNA levels were significantly correlated to plasma glucose both acutely and after 3 months (r = 0.12 and r = 0.17, both p < 0.02), whereas MPO-DNA was not. No associations with the glucometabolic status were encountered for dsDNA and MPO-DNA acutely, but after 3 months dsDNA levels were elevated in patients with IFG and T2DM vs. NGR (428 vs. 371 ng/ml and 408 vs. 371 ng/ml, both p < 0.045). During the acute glucose load after 3 months, dsDNA and MPO-DNA remained unchanged while PAD4 mRNA increased significantly (RQ 0.836 vs. 0.920, p = 0.02). CONCLUSIONS: In this cohort of STEMI patients, levels of dsDNA associated with plasma glucose both in the acute and stable condition. The glucometabolic status was not substantially related to the selected NETs markers, however, an acute glucose load by OGTT performed after 3 months resulted in increased PAD4 expression, suggestive of enhanced NETosis in the aftermath of STEMI. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT00926133 . Registered June 23, 2009.

Neutrophil Extracellular Trap Components Associate with Infarct Size, Ventricular Function, and Clinical Outcome in STEMI.

BACKGROUND: The relevance of neutrophil extracellular traps (NETs) in acute ST-elevation myocardial infarction (STEMI) is unclear. We explored the temporal profile of circulating NET markers and their associations to myocardial injury and function and to adverse clinical events in STEMI patients. METHODS AND RESULTS: In 259 patients, blood samples were drawn before and after PCI, on day 1, and after 4 months. Double-stranded deoxyribonucleic acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) were measured in serum by a nucleic acid stain and ELISA. Cardiac magnetic resonance imaging assessed microvascular obstruction (MVO), area at risk, infarct size, myocardial salvage index, left ventricular ejection fraction (LVEF), and change in indexed left ventricular end-diastolic volume (LVEDVi). Clinical events were registered after 12 months. dsDNA and MPO-DNA levels were highest before PCI, with reduced levels thereafter (all p ≤ 0.02). Patients with high vs. low day 1 dsDNA levels (>median; 366 ng/ml) more frequently had MVO, larger area at risk, larger infarct size acutely and after 4 months, and lower myocardial salvage index (all p < 0.03). Moreover, they had lower LVEF acutely and after 4 months, and larger change in LVEDVi (all p ≤ 0.014). High day 1 dsDNA levels also associated with risk of having a large infarct size (>75th percentile) and low LVEF (≤49%) after 4 months when adjusted for gender, time from symptoms to PCI, and infarct localization (OR 2.3 and 3.0, both p < 0.021), and patients with high day 1 dsDNA levels were more likely to experience an adverse clinical event, also when adjusting for peak troponin T (hazard ratio 5.1, p = 0.012). No such observations were encountered for MPO-DNA. CONCLUSIONS: High day 1 dsDNA levels after STEMI were associated with myocardial infarct size, adverse left ventricular remodeling, and clinical outcome. Although the origin of dsDNA could be discussed, these observations indicate a potential role for dsDNA in acute myocardial ischemia. This trial is registered with S-08421d, 2008/10614 (Regional Committee for Medical Research Ethics in South-East Norway (2008)).

Comparison of three haemodynamic monitoring methods in comatose post cardiac arrest patients.

OBJECTIVES: Haemodynamic monitoring during post arrest care is important to optimise treatment. We compared stroke volume measured by minimally-invasive monitoring devices with or without thermodilution calibration, and transthoracic echocardiography (TTE), and hypothesised that thermodilution calibration would give stroke volume index (SVI) more in agreement with TTE during targeted temperature management (TTM). DESIGN: Comatose out-of-hospital cardiac arrest survivors receiving TTM (33 °C for 24 hrs) underwent haemodynamic monitoring with arterial pulse contour analyses with (PiCCO2®) and without (FloTrac®/Vigileo® monitor®) transpulmonary thermodilution calibration. Haemodynamic parameters were collected simultaneously every fourth hour during TTM (hypothermia) and (normothermia). SVI was measured with TTE during hypothermia and normothermia. Bland-Altman analyses were used for determination of SVI bias (±1SD). RESULTS: Twenty-six patients were included, of whom 77% had initial shockable rhythm and 52% discharged with good outcome. SVI (bias ±2SD) between PiCCO (after thermodilution calibration) vs FloTrac/Vigileo, TTE vs FloTrac/Vigileo and TTE vs PiCCO were 1.4 (±25.8), -1.9 (±19.8), 0.06 (±18.5) ml/m2 during hypothermia and 9.7 (±23.9), 1.0 (±17.4), -7.2 (±12.8) ml/m2 during normothermia. Continuous SVI measurements between PiCCO and FloTrac/Vigileo during hypothermia at reduced SVI (<35 ml/m2) revealed low bias and relatively narrow limits of agreement (0.5 ± 10.2 ml/m2). CONCLUSION: We found low bias, but relatively wide limits of agreement in SV with PiCCO, FloTrac/Vigileo and TTE during TTM treatment. The methods are not interchangeable. Precision was not improved by transpulmonary thermodilution calibration during hypothermia.

Urine biomarkers give early prediction of acute kidney injury and outcome after out-of-hospital cardiac arrest.

BACKGROUND: Post-resuscitation care after out-of-hospital cardiac arrest (OHCA) is challenging due to the threat of organ failure and difficult prognostication. Our aim was to examine whether urine biomarkers could give an early prediction of acute kidney injury (AKI) and outcome. METHODS: This was a prospective observational study of comatose OHCA patients at Oslo University Hospital Ullevål, Norway. Risk factors were clinical parameters and biomarkers measured in spot urine (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL) and the product of tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7)) at admission and day 3. Outcome variables were AKI within 3 days using the Kidney Disease Improving Global Outcomes definition, 6-month mortality, and poor neurological outcome (PNO) defined as cerebral performance category 3-5. RESULTS: Among 195 included patients (85 % males, mean age 60 years), 88 (45 %) died, 96 (49 %) had PNO, and 88 (45 %) developed AKI. In univariate analysis, increased urine cystatin C and NGAL concentration sampled at admission and day 3 were independent risk factors for AKI, mortality and PNO. Increased urine TIMP-2 × IGFBP7 levels was associated with AKI only at admission. In multivariate analyses combining clinical parameters and biomarker concentrations, the area under the receiver operating characteristics curve (AuROC) with 95 % confidence interval (CI) were 0.774 (0.700-0.848), 0.812 (0.751-0.873), and 0.819 (0.759-0.878) for AKI, mortality and PNO, respectively. CONCLUSIONS: In comatose OHCA patients, urine levels of cystatin C and NGAL at admission and day 3 were independent risk factors for AKI, 6-month mortality and PNO. TRIAL REGISTRATION: Clinicaltrials.gov NCT01239420 . Registered 10 November 2010.

Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest.

OBJECTIVE: Comatose patients resuscitated after out-of-hospital cardiac arrest receive therapeutic hypothermia. Bradycardia is frequent during therapeutic hypothermia, but its impact on outcome remains unclear. We explore a possible association between bradycardia during therapeutic hypothermia and neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. DESIGN: Retrospective cohort study, from January 2009 to January 2011. SETTING: University hospital medical and cardiac ICUs. PATIENTS: One hundred eleven consecutive comatose out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. INTERVENTIONS: Patients treated with standardized treatment protocol after cardiac arrest. MEASUREMENTS AND MAIN RESULTS: All out-of-hospital cardiac arrest patients' records were reviewed. Hemodynamic data were obtained every fourth hour during the first days. The patients were in temperature target range (32-34°C) 8 hours after out-of-hospital cardiac arrest and dichotomized into bradycardia and nonbradycardia groups depending on their actual heart rate less than or equal to 60 beats/min or more than 60 beats/min at that time. Primary endpoint was Cerebral Performance Category score at hospital discharge. More nonbradycardia group patients received epinephrine during resuscitation and epinephrine and norepinephrine in the early in-hospital period. They also had lower base excess at admission. Survival rate with favorable outcome was significantly higher in the bradycardia than the nonbradycardia group (60% vs 37%, respectively, p = 0.03). For further heart rate quantification, patients were divided into quartiles: less than or equal to 49 beats/min, 50-63 beats/min, 64-77 beats/min, and more than or equal to 78 beats/min, with respective proportions of patients with good outcome at discharge of 18 of 27 (67%), 14 of 25 (56%), 12 of 28 (43%), and 7 of 27 (26%) (p = 0.002). Patients in the lowest quartile had significantly better outcome than the higher groups (p = 0.027), whereas patients in the highest quartile had significantly worse outcome than the lower three groups (p = 0.013). CONCLUSIONS: Bradycardia during therapeutic hypothermia was associated with good neurologic outcome at hospital discharge. Our data indicate that bradycardia should not be aggressively treated in this period if mean arterial pressure, lactate clearance, and diuresis are maintained at acceptable levels. Studies, both experimental and clinical, are warranted.

Effects of mild hypercapnia on myocardial injury after out-of-hospital cardiac arrest. A sub-study of the TAME trial.

PURPOSE: Mild hypercapnia did not improve neurological outcomes for resuscitated out-of-hospital cardiac arrest (OHCA) patients in the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. However, the effects of hypercapnic acidosis on myocardial injury in patients with cardiac arrest is unexplored. We investigated whether mild hypercapnia compared to normocapnia, following emergency coronary intervention, increased myocardial injury in comatose OHCA-patients with AMI. METHODS: Single-centre, prospective, pre-planned sub-study of the TAME trial. Patients were randomised to targeted mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 h. Myocardial injury was assessed with high-sensitive cardiac troponin T (hs-cTnT) measured at baseline, 24, 48 and 72 h. Haemodynamics were assessed with right heart catheterisation and blood-gas analyses every 4th hour for 48 h. RESULTS: We included 125 OHCA-patients. 57 (46%) had an AMI, with 31 and 26 patients randomised to hypercapnia and normocapnia, respectively. Median peak hs-cTnT in AMI-patients was 58% lower in the hypercapnia-group: 2136 (IQR: 861-4462) versus 5165 ng/L (IQR: 2773-7519), p = 0.007. Lower average area under the hs-cTnT curve was observed in the hypercapnia-group: 2353 (95% CI 1388-3319) versus 4953 ng/L (95% CI 3566-6341), P-group = 0.002. Hypercapnia was associated with increased cardiac power output (CPO) and lower lactate levels in patients with AMI (P-group < 0.05). hs-cTnT, lactate and CPO were not significantly different between intervention groups in OHCA-patients without AMI (p > 0.05). CONCLUSIONS: Mild hypercapnia was not associated with increased myocardial injury in resuscitated OHCA-patients. In AMI-patients, mild hypercapnia was associated with lower hs-cTnT and lactate, and improved cardiac performance. TRIAL REGISTRATION NUMBER: NCT03114033.

Transcranial Doppler during the first week after cardiac arrest and association with 6-month outcomes.

Background: Early prediction of outcomes in comatose patients after out-of-hospital cardiac arrest is challenging. Prognostication tools include clinical examination, biomarkers, and neuroradiological and neurophysiological tests. We studied the association between transcranial Doppler (TCD) and the outcome. Methods: This was a pre-defined sub-study of the prospective observational Norwegian Cardiorespiratory Arrest Study. Patients underwent standardized post-resuscitation care, including target temperature management (TTM) to 33°C for 24 h. TCD was performed at days 1, 3, and 5-7. The primary endpoint was cerebral performance category (CPC) at 6 months, dichotomized into good (CPC 1-2) and poor (CPC 3-5) outcomes. We used linear mixed modeling time-series analysis. Results: Of 139 TCD-examined patients, 81 (58%) had good outcomes. Peak systolic velocity in the middle cerebral artery (PSV) was low during TTM (Day 1) and elevated after rewarming (Day 3). Thereafter, it continued to rise in patients with poor, but normalized in patients with good, outcomes. At days 5-7, PSV was 1.0 m/s (95% CI 0.9; 1.0) in patients with good outcomes and 1.3 m/s (95% CI 1.1; 1.4) in patients with poor outcomes (p < 0.001). Conclusion: Elevated PSV at days 5-7 indicated poor outcomes. Our findings suggest that serial TCD examinations during the first week after cardiorespiratory arrest may improve our understanding of serious brain injury.

Cardiovascular changes induced by targeted mild hypercapnia after out of hospital cardiac arrest. A sub-study of the TAME cardiac arrest trial.

AIM: Hypercapnia may elicit detrimental haemodynamic effects in critically ill patients. We aimed to investigate the consequences of targeted mild hypercapnia versus targeted normocapnia on pulmonary vascular resistance and right ventricular function in patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: Pre-planned, single-centre, prospective, sub-study of the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. Patients were randomised to mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 hours. Haemodynamic assessment was performed with right heart catheterisation and serial blood-gas analyses every4th hour for 48 hours. RESULTS: We studied 84 patients. Mean pH was 7.24 (95% CI 7.22-7.30) and 7.32 (95% CI 7.31-7.34) with hypercapnia and normocapnia, respectively (P-group < 0.001). Pulmonary vascular resistance index (PVRI), pulmonary artery pulsatility index, and right atrial pressure did not differ between groups (P-group > 0.05). Mean cardiac index was higher with mild hypercapnia (P-group < 0.001): 2.0 (95% CI 1.85-2.1) vs 1.6 (95% CI 1.52-1.76) L/min/m2. Systemic vascular resistance index was 2579 dyne-sec/cm-5/ m2 (95% CI 2356-2830) with hypercapnia, and 3249 dyne-sec/cm-5/ m2 (95% CI 2930-3368) with normocapnia (P-group < 0.001). Stroke volumes (P-group = 0.013) and mixed venous oxygen saturation (P-group < 0.001) were higher in the hypercapnic group. CONCLUSION: In resuscitated OHCA patients, targeting mild hypercapnia did not increase PVRI or worsen right ventricular function compared to normocapnia. Mild hypercapnia comparatively improved cardiac performance and mixed venous oxygen saturation.

Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab.

BACKGROUND: Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. METHODS: STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. RESULTS: Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively). CONCLUSIONS: Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients. TRIAL REGISTRATION NUMBER: NCT03004703.

[A woman with a chronic cough and dyspnoea]. / En kvinne med kronisk hoste og dyspné.

A previously healthy woman in her forties with a six-month history of persistent coughing, breathlessness and fatigue was referred to our hospital for further evaluation. She was initially treated with antibiotics for a possible respiratory tract infection but with only minor effect. A chest x-ray and computer tomography (CT) of the thorax demonstrated a solid tumour in the right lung hilus. Bronchoscopy revealed slight oedema of the bronchial mucous membrane in the area in question. Cytological examination of bronchoalveolar lavage fluid (BAL) showed normal respiratory epithelial cells. Histological examination of a needle biopsy from the tumour showed lymphoproliferative changes of uncertain cause. Magnetic resonance imaging (MRI) of the thorax provided no further information. An electrocardiogram (ECG) revealed signs of left ventricular hypertrophy and sinus bradycardia. Her complaints were palpitations, mild exertional dyspnoea and attenuated heart rate response to exercise. Echocardiography showed increased wall thickness with heterogeneous echogenicity in both ventricles, a slightly enlarged left atrium and mild mitral regurgitation. Tissue Doppler measurements showed impaired relaxation. These findings were suggestive of restrictive cardiomyopathy with diastolic dysfunction. Cardiac MRI confirmed the echocardiographic findings. The tumour was removed by thoracotomy and was shown to be made up of lymphatic tissue with granulomas, consistent with sarcoidosis. The restrictive cardiomyopathy was regarded as a cardiac manifestation of sarcoidosis. The patient was treated with corticosteroids. Clinical follow up with cardiac MRI and echocardiography did not reveal any progression of the cardiac involvement. Cardiac sarcoidosis must be considered in all sarcoid patients because of its significance for prognosis and treatment.

Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

BACKGROUND: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone. MATERIALS AND METHODS: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean. RESULTS: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio. CONCLUSION: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.

Changes in health status and health related quality of life from six months to five years in out-of-hospital cardiac arrest survivors - A NORCAST sub study.

BACKGROUND: Brain injury in out-of-hospital cardiac arrest (OHCA) survivors affects health status and health-related quality of life (HRQoL). It is unknown how HRQoL evolves over time, and assessments at different time points may lead to different results. METHODS: In a NORCAST sub study, OHCA survivors eligible for health status (EQ-5D-3L) and HRQoL (SF-36) assessments were examinated six months and five years after OHCA. At five-year follow-up, survivors also retrospectively assessed their health status for each consecutive year following OHCA. The next of kin independently assessed health status and HRQoL of their respective OHCA survivors. RESULTS: Among 138 survivors alive after six months and 117 after five years, 80 (88% male) completed both follow-ups. Health status and HRQoL remained stable over time, except for increasing SF-36 mental summary score and decreasing physical functioning and physical component score. Anxiety and depression levels were generally low, although younger survivors stated more anxiety than older survivors. Retrospective assessment showed reduced health status for the first two years, which increased only from the third year. Explorative analyses revealed that younger age, longer time to return of spontaneous circulation (tROSC) and late awakening affected health status, particularly in the first two years post-arrest. CONCLUSIONS: OHCA survivors showed stable health status and HRQoL with only minor differences between six months and five years. Younger survivors with long tROSC, late awakening, and more anxiety and depression symptoms at six months, had reduced health status the first two years with significant improvements towards the fourth year.

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

BACKGROUND: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. METHODS: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). FINDINGS: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. INTERPRETATION: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. FUNDING: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI.

OBJECTIVE: Inflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI. METHODS: We included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively. RESULTS: IL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality. CONCLUSION: Acute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention. TRIAL REGISTRATION NUMBER: NCT00922675.

Case report: a patient with thyroid storm, refractory cardiogenic shock, and cardiac arrest treated with Lugol's iodine solution and veno-arterial extra corporal membrane oxygenation support.

BACKGROUND: Thyroid storm is a life-threatening condition. Refractory cardiogenic shock and cardiac arrest are rare complications of thyroid storm and the treatment options are limited. CASE SUMMARY: A 35-year- old woman treated for Grave's disease was admitted with thyrotoxicosis complicated by infection and neutropenia caused by thionamide treatment. After treatment including beta-blockers, steroids, and Lugol's iodine solution, she went into cardiac arrest. Echocardiography after resuscitation demonstrated severe biventricular heart failure. The patient was in refractory cardiogenic shock with recurrent cardiac arrest and mechanical circulatory support with a veno-arterial extra corporal membrane oxygenation (V-A ECMO) circuit was established. After 2 days on V-A ECMO and supportive treatment with iodine solution, glucocorticosteroids, and levosimendan, her myocardial function recovered and thyroid hormone levels were normalized. Veno-arterial extra corporal membrane oxygenation was discontinued, and the patient was treated with early total thyroidectomy. The patient made a full recovery with no neurological/cognitive impairment, as assessed after 4 weeks. DISCUSSION: Adverse reactions to standard treatment of hyperthyroidism contributed to this patient's development of thyroid storm and the following refractory cardiogenic shock. When she was critically unstable, levosimendan improved myocardial function while inotropic support with dobutamine was ineffective, likely due to prolonged beta-antagonist administration. Temporary support with V-A ECMO, until effective lowering of thyroid hormone levels and improvement in myocardial function were obtained, was life-saving in this young patient and may be considered in refractory cardiogenic shock caused by thyroid storm.