Association between speckle tracking echocardiography and pressure-volume loops during cardiogenic shock development.

BACKGROUND: The relationship between speckle tracking assessed global longitudinal strain (GLS) and Doppler-based echocardiography with basic physiological markers of cardiac function derived from pressure-volume loops is poorly elucidated. OBJECTIVE: We aimed to describe the association between LS and Doppler-based echocardiography and direct measurements of central haemodynamic parameters from conductance catheter-based pressure-volume loops in an animal model with increasing left ventricular (LV) dysfunction. METHODS: 12 Danish landrace female pigs (75-80 kg) were used. All instrumentations were performed percutaneously, including the conductance catheter in the LV. Progressive LV dysfunction was induced by embolisation through the left main coronary artery with microspheres every 3 min until a >50% reduction in cardiac output (CO) or mixed venous saturation (SvO2), compared with baseline, or SvO2 <30%. Echocardiography was performed at baseline and 90 s after each injection. RESULTS: With progressive LV dysfunction, mean CO decreased from 5.6±0.9 L/min to 2.1±0.9 L/min, and mean SvO2 deteriorated from 61.1±7.9% to 35.3±6.1%. Mean LS and LV outflow tract velocity time integral (LVOT VTI) declined from -13.8±3.0% to -6.1±2.0% and 16.9±2.6 cm to 7.8±1.8 cm, respectively. LS and LVOT VTI showed the strongest correlation to stroke work in unadjusted linear regression (r2=0.53 and r2=0.49, respectively). LS correlated significantly with stroke volume, end-systolic elastance, systolic blood pressure, ventriculo-arterial coupling and arterial elastance. CONCLUSION: In an animal model of acute progressive LV dysfunction, echocardiographic and conductance catheter-based measurements changed significantly. LS and LVOT VTI displayed the earliest and the largest alterations with increased myocardial damage and both correlated strongest with stroke work.

Immediate inflammatory response to mechanical circulatory support in a porcine model of severe cardiogenic shock.

BACKGROUND: In selected cases of cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is combined with trans valvular micro axial flow pumps (ECMELLA). Observational studies indicate that ECMELLA may reduce mortality but exposing the patient to two advanced mechanical support devices may affect the early inflammatory response. We aimed to explore inflammatory biomarkers in a porcine cardiogenic shock model managed with V-A ECMO or ECMELLA. METHODS: Fourteen landrace pigs had acute myocardial infarction-induced cardiogenic shock with minimal arterial pulsatility by microsphere embolization and were afterwards managed 1:1 with either V-A ECMO or ECMELLA for 4 h. Serial blood samples were drawn hourly and analyzed for serum concentrations of interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha, and serum amyloid A (SAA). RESULTS: An increase in IL-6, IL-8, and SAA levels was observed during the experiment for both groups. At 2-4 h of support, IL-6 levels were higher in ECMELLA compared to V-A ECMO animals (difference: 1416 pg/ml, 1278 pg/ml, and 1030 pg/ml). SAA levels were higher in ECMELLA animals after 3 and 4 h of support (difference: 401 ng/ml and 524 ng/ml) and a significant treatment-by-time effect of ECMELLA on SAA was identified (p = 0.04). No statistical significant between-group differences were observed in carotid artery blood flow, urine output, and lactate levels. CONCLUSIONS: Left ventricular unloading with Impella during V-A ECMO resulted in a more extensive inflammatory reaction despite similar end-organ perfusion.

Haemodynamic implications of VA-ECMO vs. VA-ECMO plus Impella CP for cardiogenic shock in a large animal model.

AIMS: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) with profound left ventricular (LV) failure is associated with inadequate LV emptying. To unload the LV, VA-ECMO can be combined with Impella CP (ECMELLA). We hypothesized that ECMELLA improves cardiac energetics compared with VA-ECMO in a porcine model of cardiogenic shock (CS). METHODS AND RESULTS: Land-race pigs (weight 70 kg) were instrumented, including a LV conductance catheter and a carotid artery Doppler flow probe. CS was induced with embolization in the left main coronary artery. CS was defined as reduction of ≥50% in cardiac output or mixed oxygen saturation (SvO2) or a SvO2 < 30%. At CS VA-ECMO was initiated and embolization was continued until arterial pulse pressure was <10 mmHg. At this point, Impella CP was placed in the ECMELLA arm. Support was maintained for 4 h. CS was induced in 15 pigs (VA-ECMO n = 7, ECMELLA n = 8). At time of CS MAP was <45 mmHg in both groups, with no difference at 4 h (VA-ECMO 64 mmHg ± 11 vs. ECMELLA 55 mmHg ± 21, P = 0.08). Carotid blood flow and arterial lactate increased from CS and was similar in VA-ECMO and ECMELLA [239 mL/min ± 97 vs. 213 mL/min ± 133 (P = 0.6) and 5.2 ± 3.3 vs. 4.2 ± 2.9 mmol/ (P = 0.5)]. Pressure-volume area (PVA) was significantly higher with VA-ECMO compared with ECMELLA (9567 ± 1733 vs. 6921 ± 5036 mmHg × mL/min × 10-3, P = 0.014). Total diureses was found to be lower in VA-ECMO compared with ECMELLA [248 mL (179-930) vs. 506 mL (418-2190); P = 0.005]. CONCLUSIONS: In a porcine model of CS, we found lower PVA, with the ECMELLA configuration compared with VA-ECMO, indicating better cardiac energetics without compromising systemic perfusion.

Return to Work After Refractory Out-of-Hospital Cardiac Arrest in Patients Managed With or Without Extracorporeal Cardiopulmonary Resuscitation: A Nationwide Register-Based Study.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly used for refractory out-of-hospital cardiac arrest (OHCA). However, survivors managed with ECPR are at risk of poor functional status. The purpose of this study was to investigate return to work (RTW) after refractory OHCA. METHODS AND RESULTS: Of 44 360 patients with OHCA in the period of 2011 to 2020, this nationwide registry-based study included 805 patients with refractory OHCA in the working age (18-65 years) who were employed before OHCA (2% of the total OHCA cohort). Demographics, prehospital characteristics, status at hospital arrival, employment status, and survival were retrieved through the Danish national registries. Sustainable RTW was defined as RTW for ≥6 months without any long sick leave relapses. Median follow-up time was 4.1 years. ECPR and standard advanced cardiovascular life support were applied in 136 and 669 patients, respectively. RTW 1 year after OHCA was similar (39% versus 54%; P=0.2) and sustainable RTW was high in both survivors managed with ECPR and survivors managed with standard advanced cardiovascular life support (83% versus 85%; P>0.9). Younger age and shorter length of hospitalization were associated with RTW in multivariable Cox analysis, whereas ECPR was not. CONCLUSIONS: In refractory OHCA-patients employed prior to OHCA, approximately 1 out of 2 patients were employed after 1 year with no difference between patients treated with ECPR or standard advanced cardiovascular life support. Younger age and shorter length of hospitalization were associated with RTW while ECPR was not.

Health-related quality of life and cognitive function after out-of-hospital cardiac arrest; a comparison of prehospital return-of-spontaneous circulation and refractory arrest managed with extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for selected refractory out-of-hospital cardiac arrest (OHCA) is increasingly used. Detailed knowledge of health-related quality of life (HRQoL) and long-term cognitive function is limited. HRQoL and cognitive function were assessed in ECPR-survivors and OHCA-survivors with prehospital return of spontaneous circulation after standard advanced cardiac life support (sACLS). METHODS: Fifteen ECPR-survivors and 22 age-matched sACLS-survivors agreed to participate in this follow-up study. Participants were examined with echocardiography, 6-minute walk test, and neuropsychological testing, and answered HRQoL (EQ-5D-5L and Short Form 36 (SF-36)), and mental health questionnaires. RESULTS: Most patients were male (73 % and 82 %) and median age at follow-up was similar between groups (55 years and 60 years). Low flow time was significantly longer for ECPR-survivors (86 min vs. 15 min) and lactate levels were significantly higher (14.1 mmol/l vs. 3.9 mmol/l). No between-group difference was found in physical function nor in cognitive function with scores corresponding to the 23rd worst percentile of the general population. SACLS-survivors had HRQoL on level with the Danish general population while ECPR-survivors scored lower in both EQ-5D-5L (index score 0.73 vs. 0.86, p = 0.03, visual analog scale: 70 vs. 84, p = 0.04) and in multiple SF-36 health domains (role physical, bodily pain, general health, and mental health). CONCLUSIONS: Despite substantially longer low flow times with thrice as high lactate levels, ECPR-survivors were similar in cognitive and physical function compared to sACLS-survivors. Nonetheless, ECPR-survivors reported lower HRQoL overall and related to mental health, pain management, and the perception of limitations in physical role.

Lactate and lactate clearance as predictors of one-year survival in extracorporeal cardiopulmonary resuscitation - An international, multicentre cohort study.

AIM: Extracorporeal cardiopulmonary resuscitation (ECPR) can be considered in selected patients with refractory cardiac arrest. Given the risk of patient futility and high resource utilisation, identifying ECPR candidates, who would benefit from this therapy, is crucial. Previous ECPR studies investigating lactate as a potential prognostic marker have been small and inconclusive. In this study, it was hypothesised that the lactate level (immediately prior to initiation of ECPR) and lactate clearance (within 24 hours after ECPR initiation) are predictors of one-year survival in a large, multicentre study cohort of ECPR patients. METHODS: Adult patients with refractory cardiac arrest at three German and four Danish tertiary cardiac care centres between 2011 and 2021 were included. Pre-ECPR lactate and 24-hour lactate clearance were divided into three equally sized tertiles. Multivariable logistic regression analyses and Kaplan-Meier analyses were used to analyse survival outcomes. RESULTS: 297 adult patients with refractory cardiac arrest were included in this study, of which 65 (22%) survived within one year. The pre-ECPR lactate level and 24-hour lactate clearance were level-dependently associated with one-year survival: OR 5.40 [95% CI 2.30-13.60] for lowest versus highest pre-ECPR lactate level and OR 0.25 [95% CI 0.09-0.68] for lowest versus highest 24-hour lactate clearance. Results were confirmed in Kaplan-Meier analyses (each p log rank < 0.001) and subgroup analyses. CONCLUSION: Pre-ECPR lactate levels and 24 hour-lactate clearance after ECPR initiation in patients with refractory cardiac arrest were level-dependently associated with one-year survival. Lactate is an easily accessible and quickly available point-of-care measurement which might be considered as an early prognostic marker when considering initiation or continuation of ECPR treatment.

Left-Ventricular Unloading With Impella During Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation (ECPR) is the implementation of venoarterial extracorporeal membrane oxygenation (VA-ECMO) during refractory cardiac arrest. The role of left-ventricular (LV) unloading with Impella in addition to VA-ECMO ("ECMELLA") remains unclear during ECPR. This is the first systematic review and meta-analysis to characterize patients with ECPR receiving LV unloading and to compare in-hospital mortality between ECMELLA and VA-ECMO during ECPR. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, and abstract websites of the three largest cardiology societies (American Heart Association, American College of Cardiology, and European Society of Cardiology). STUDY SELECTION: Observational studies with adult patients with refractory cardiac arrest receiving ECPR with ECMELLA or VA-ECMO until July 2023 according to the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. DATA EXTRACTION: Patient and treatment characteristics and in-hospital mortality from 13 study records at 32 hospitals with a total of 1014 ECPR patients. Odds ratios (ORs) and 95% CI were computed with the Mantel-Haenszel test using a random-effects model. DATA SYNTHESIS: Seven hundred sixty-two patients (75.1%) received VA-ECMO and 252 (24.9%) ECMELLA. Compared with VA-ECMO, the ECMELLA group was comprised of more patients with initial shockable electrocardiogram rhythms (58.6% vs. 49.3%), acute myocardial infarctions (79.7% vs. 51.5%), and percutaneous coronary interventions (79.0% vs. 47.5%). VA-ECMO alone was more frequently used in pulmonary embolism (9.5% vs. 0.7%). Age, rate of out-of-hospital cardiac arrest, and low-flow times were similar between both groups. ECMELLA support was associated with reduced odds of mortality (OR, 0.53 [95% CI, 0.30-0.91]) and higher odds of good neurologic outcome (OR, 2.22 [95% CI, 1.17-4.22]) compared with VA-ECMO support alone. ECMELLA therapy was associated with numerically increased but not significantly higher complication rates. Primary results remained robust in multiple sensitivity analyses. CONCLUSIONS: ECMELLA support was predominantly used in patients with acute myocardial infarction and VA-ECMO for pulmonary embolism. ECMELLA support during ECPR might be associated with improved survival and neurologic outcome despite higher complication rates. However, indications and frequency of ECMELLA support varied strongly between institutions. Further scientific evidence is urgently required to elaborate standardized guidelines for the use of LV unloading during ECPR.

Selection of patients for mechanical circulatory support for refractory out-of-hospital cardiac arrest.

OBJECTIVE: To describe characteristics of patients admitted with refractory cardiac arrest for possible extracorporeal cardiopulmonary resuscitation (ECPR) and gain insight into the reasons for refraining from treatment in some. METHODS: Nationwide retrospective cohort study involving all tertiary centres providing ECPR in Denmark. Consecutive patients admitted with ongoing chest compression for evaluation for ECPR treatment were enrolled. Presenting characteristics, duration of no-flow and low-flow time, end-tidal carbon dioxide (ETCO2), lactate and pH, and recording of reasons for refraining from ECPR documented by the treating team were recorded. Outcomes were survival to intensive care unit admission and survival to hospital discharge. RESULTS: Of 579 patients admitted with refractory cardiac arrest for possible ECPR, 221 patients (38%) proceeded to ECPR and 358 patients (62%) were not considered candidates. Median prehospital low-flow time was 70 min (IQR 56 to 85) in ECPR patients and 62 min (48 to 81) in no-ECPR patients, p<0.001. Intra-arrest transport was more than 50 km in 92 (42%) ECPR patients and 135 in no-ECPR patients (38%), p=0.25. The leading causes for not initiating ECPR stated by the treating team were duration of low-flow time in 39%, severe metabolic derangement in 35%, and in 31% low ETCO2. The prevailing combination of contributing factors were non-shockable rhythm, low ETCO2, and metabolic derangement or prehospital low-flow time combined with low ETCO2. Survival to discharge was only achieved in six patients (1.7%) in the no-ECPR group. CONCLUSIONS: In this large nationwide study of patients admitted for possible ECPR, two-thirds of patients were not treated with ECPR. The most frequent reasons to abstain from ECPR were long duration of prehospital low-flow time, metabolic derangement and low ETCO2.

Extracorporeal cardiopulmonary resuscitation: a national study on the association between favourable neurological status and biomarkers of hypoperfusion, inflammation, and organ injury.

AIMS: In refractory out-of-hospital cardiac arrest (OHCA) with prolonged whole-body ischaemia, global tissue injury proceeds even after establishment of circulation with extracorporeal cardiopulmonary resuscitation (ECPR). We aimed to investigate the role of biomarkers reflecting hypoperfusion, inflammation, and organ injury in prognostication of patients with refractory OHCA managed with ECPR. METHODS AND RESULTS: This nationwide retrospective study included 226 adults with refractory OHCA managed with ECPR in Denmark (2011-2020). Biomarkers the first days after ECPR-initiation were assessed. Odds ratio of favourable neurological status (Cerebral Performance Category 1-2) at hospital discharge was estimated by logistic regression analyses. Cut-off values were calculated using the Youden's index. Fifty-six patients (25%) survived to hospital discharge, 51 (91%) with a favourable neurological status. Factors independently associated with favourable neurological status were low flow time <81 min, admission leukocytes ≥12.8 × 109/L, admission lactate <13.2 mmol/L, alkaline phosphatase (ALP) < 56 (day1) or <55 U/L (day2), and day 1 creatine kinase MB (CK-MB) < 500 ng/mL. Selected biomarkers (leukocytes, C-reactive protein, and lactate) were significantly better predictors of favourable neurological status than classic OHCA-variables (sex, age, low-flow time, witnessed arrest, shockable rhythm) alone (P = 0.001) after hospital admission. CONCLUSION: Biomarkers of hypoperfusion (lactate), inflammation (leucocytes), and organ injury (ALP and CK-MB) were independently associated with neurological status at hospital discharge. Biomarkers of hypoperfusion and inflammation (at hospital admission) and organ injury (days 1 and 2 after ECPR) may aid in the clinical decision of when to prolong or terminate ECPR in cases of refractory OHCA.

Mechanical circulatory support for refractory out-of-hospital cardiac arrest: a Danish nationwide multicenter study.

BACKGROUND: Mechanical circulatory support (MCS) with either extracorporeal membrane oxygenation or Impella has shown potential as a salvage therapy for patients with refractory out-of-hospital cardiac arrest (OHCA). The objective of this study was to describe the gradual implementation, survival and adherence to the national consensus with respect to use of MCS for OHCA in Denmark, and to identify factors associated with outcome. METHODS: This retrospective, observational cohort study included patients receiving MCS for OHCA at all tertiary cardiac arrest centers (n = 4) in Denmark between July 2011 and December 2020. Logistic regression and Kaplan-Meier survival analysis were used to determine association with outcome. Outcome was presented as survival to hospital discharge with good neurological outcome, 30-day survival and predictors of 30-day mortality. RESULTS: A total of 259 patients were included in the study. Thirty-day survival was 26%. Sixty-five (25%) survived to hospital discharge and a good neurological outcome (Glasgow-Pittsburgh Cerebral Performance Categories 1-2) was observed in 94% of these patients. Strict adherence to the national consensus showed a 30-day survival rate of 30% compared with 22% in patients violating one or more criteria. Adding criteria to the national consensus such as signs of life during cardiopulmonary resuscitation (CPR), pre-hospital low-flow < 100 min, pH > 6.8 and lactate < 15 mmol/L increased the survival rate to 48%, but would exclude 58% of the survivors from the current cohort. Logistic regression identified asystole (RR 1.36, 95% CI 1.18-1.57), pulseless electrical activity (RR 1.20, 95% CI 1.03-1.41), initial pH < 6.8 (RR 1.28, 95% CI 1.12-1.46) and lactate levels > 15 mmol/L (RR 1.16, 95% CI 1.16-1.53) as factors associated with increased risk of 30-day mortality. Patients presenting signs of life during CPR had reduced risk of 30-day mortality (RR 0.63, 95% CI 0.52-0.76). CONCLUSIONS: A high survival rate with a good neurological outcome was observed in this Danish population of patients treated with MCS for OHCA. Stringent patient selection for MCS may produce higher survival rates but potentially withholds life-saving treatment in a significant proportion of survivors.

Early ICD implantation in cardiac arrest survivors with acute coronary syndrome - predictors of implantation, ICD-therapy and long-term survival.

Objectives. Implantable cardioverter defibrillator (ICD) implantation in patients resuscitated from out-of-hospital cardiac arrest (OHCA) due to acute myocardial infarction (AMI) is controversial. Design. Consecutive OHCA-survivors due to AMI from two Danish tertiary heart centers from 2007 to 2011 were included. Predictors of ICD-implantation, ICD-therapy and long-term survival (5 years) were investigated. Patients with and without ICD-implantation during the index hospital admission were included (later described as early ICD-implantation). Patients with an ICD after hospital discharge were censored from further analyses at time of implantation. Results. We identified 1,457 consecutive OHCA-patients, and 292 (20%) of the cohort met the inclusion criteria. An ICD was implanted during hospital admission in 78 patients (27%). STEMI and successful revascularization were inversely and independently associated with ICD-implantation (ORSTEMI = 0.37, 95% CI: 0.14-0.94, ORrevasc = 0.11, 0.03-0.36) whereas age, sex, LVEF <35%, comorbidity burden or shockable first OHCA-rhythm were not associated with ICD-implantation. Appropriate ICD-shock therapy during the follow-up period was noted in 15% of patients (n = 12). Five-year mortality-rate was significantly lower in ICD-patients (18% vs. 28%, plogrank = 0.02), which was persistent after adjustment for prognostic factors (HR = 0.44 (95% CI: 0.23-0.88)). This association was no longer found when using first event (death or appropriate shock whatever came first) as outcome variable (plogrank = 0.9). Conclusions. Mortality after OHCA due to AMI was significantly lower in patients with early ICD-implantation after adjustment for prognostic factors. When using appropriate shock and death as events, ICD-patients had similar outcome as patients without an ICD, which may suggest a survival benefit due to appropriate device therapy.

Quantitative Proteomics of Human Heart Samples Collected In Vivo Reveal the Remodeled Protein Landscape of Dilated Left Atrium Without Atrial Fibrillation.

Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF).We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts.This is the largest dataset of cardiac protein expression from human samples collected in vivo It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that changes in abundance of proteins known to associate with AF are not sufficient for arrhythmogenesis.

Refractory out-of-hospital cardiac arrest with ongoing cardiopulmonary resuscitation at hospital arrival - survival and neurological outcome without extracorporeal cardiopulmonary resuscitation.

BACKGROUND: The prognosis in refractory out-of-hospital cardiac arrest (OHCA) with ongoing cardiopulmonary resuscitation (CPR) at hospital arrival is often considered dismal. The use of extracorporeal cardiopulmonary resuscitation (eCPR) for perfusion enhancement during resuscitation has shown variable results. We aimed to investigate outcome in refractory OHCA patients managed conservatively without use of eCPR. METHODS: We included consecutive OHCA patients with refractory arrest or prehospital return of spontaneous circulation (ROSC) in the Copenhagen area in 2002-2011. RESULTS: A total of 3992 OHCA patients with resuscitation attempts were included; in 2599, treatment was terminated prehospital, and 1393 (35%) were brought to the hospital either with ROSC (n = 1285, 92%) or with refractory OHCA (n = 108, 8%). Of patients brought in with refractory OHCA, 56 (52%) achieved ROSC in the emergency department. There were no differences between patients with refractory OHCA or prehospital ROSC with regard to age, sex, comorbidities, or etiology of OHCA. Time to emergency medical services (EMS) arrival was similar, whereas time to ROSC (when ROSC was achieved) was longer in refractory OHCA patients (EMS, 6 (5-9] vs. 7 [5-10] min, p = 0.8; ROSC, 15 [9-22] vs. 27 [20-41] min, p < 0.001). Independent factors associated with transport with refractory OHCA instead of prehospital termination of therapy were OHCA in public (OR, 3.6 [95% CI, 2.2-5.8]; p < 0.001), witnessed OHCA (OR, 3.7 [2.0-7.1]; p < 0.001), shockable rhythm (OR, 3.0 [1.9-4.7]; p < 0.001), younger age (OR, 1.2 [1.1-1.2]; p < 0.001), and later calendar year (OR, 1.4 [1.2-1.6]; p < 0.001). Thirty-day survival was 20% in patients with refractory OHCA compared with 42% in patients with prehospital ROSC (p < 0.001). Four of 28 refractory OHCA patients with duration of resuscitation > 60 min achieved ROSC. No difference in favorable neurological outcome in patients surviving to discharge was found (prehospital ROSC 84% vs. refractory OHCA 86%; p = 0.7). CONCLUSIONS: Survival after refractory OHCA with ongoing CPR at hospital arrival was significantly lower than among patients with prehospital ROSC. Despite a lower survival, the majority of survivors with both refractory OHCA and prehospital ROSC were discharged with a similar degree of favorable neurological outcome, indicating that continued efforts in spite of refractory OHCA are not in vain and may still lead to favorable outcome even without eCPR.

Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown. OBJECTIVE: The purpose of this study was to investigate the prevalence of somatic variants in AF candidate genes in an AF patient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF. METHODS: DNA was extracted from blood and left atrial tissue from 44 AF patients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques. RESULTS: No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1 candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2). CONCLUSION: We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AF patients might, like lone AF patients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.

pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts.

In isolated human atrial cardiomyocytes, inhibition of K2P3.1 K(+) channels results in action potential (action potential duration (APD)) prolongation. It has therefore been postulated that K2P3.1 (KCNK3), together with K2P9.1 (KCNK9), could represent novel drug targets for the treatment of atrial fibrillation (AF). However, it is unknown whether these findings in isolated cells translate to the whole heart. The purposes of this study were to investigate the expression levels of KCNK3 and KCNK9 in human hearts and two relevant rodent models and determine the antiarrhythmic potential of K2P3.1 inhibition in isolated whole-heart preparations. By quantitative PCR, we found that KCNK3 is predominantly expressed in human atria whereas KCNK9 was not detectable in heart human tissue. No differences were found between patients in AF or sinus rhythm. The expression in guinea pig heart resembled humans whereas rats displayed a more uniform expression of KCNK3 between atria and ventricle. In voltage-clamp experiments, ML365 and A293 were found to be potent and selective inhibitors of K2P3.1, but at pH 7.4, they failed to prolong atrial APD and refractory period (effective refractory period (ERP)) in isolated perfused rat and guinea pig hearts. At pH 7.8, which augments K2P3.1 currents, pharmacological channel inhibition produced a significant prolongation of atrial ERP (11.6 %, p = 0.004) without prolonging ventricular APD but did not display a significant antiarrhythmic effect in our guinea pig AF model (3/8 hearts converted on A293 vs 0/7 hearts in time-matched controls). These results suggest that when K2P3.1 current is augmented, K2P3.1 inhibition leads to atrial-specific prolongation of ERP; however, this ERP prolongation did not translate into significant antiarrhythmic effects in our AF model.

Adipose tissue mitochondrial respiration and lipolysis before and after a weight loss by diet and RYGB.

OBJECTIVE: To study adipose tissue mitochondrial respiration and lipolysis following a massive weight loss. METHODS: High resolution respirometry of adipose tissue biopsies and tracer determined whole body lipolysis. Sixteen obese patients with type 2 diabetes (T2DM) and 27 without (OB) were studied following a massive weight loss by diet and Roux-en-Y gastric bypass (RYGB). RESULTS: The mitochondrial respiratory rates were similar in OB and T2DM, and the mass-specific oxygen flux increased significantly 4 and 18 months post-surgery (P < 0.05). With normalization to mitochondrial content, no differences in oxidative capacity after RYGB were seen. The ratio between the oxidative phosphorylation system capacity (P) and the capacity of the electron transfer system (E) increased 18 months after RYGB in both groups (P < 0.05). Lipolysis per fat mass was similar in the two groups and was increased (P < 0.05) and lipid oxidation during hyperinsulinemia decreased 4 months post-surgery. In T2DM, visceral fat mass was always higher relative to the body fat mass (%) compared to OB. CONCLUSIONS: Adipose tissue mitochondrial respiratory capacity increases with RYGB. Adipocytes adapt to massive weight loss by increasing the phosphorylation system ratio (P/E), suggesting an increased ability to oxidize substrates after RYGB. Lipolysis increases in the short term post-surgery, and insulin sensitivity for suppression of lipolysis increases with RYGB.