Human Plasma Metabolomics Identify 9-cis-retinoic Acid and Dehydrophytosphingosine Levels as Novel biomarkers for Early Ventricular Fibrillation after ST-elevated Myocardial Infarction.

The relevant metabolite biomarkers for risk prediction of early onset of ventricular fibrillation (VF) after ST-segment elevation myocardial infarction (STEMI) remain unstudied. Here, we aimed to identify these imetabolites and the important metabolic pathways involved, and explore whether these metabolites could be used as predictors for the phenotype. Plasma samples were obtained retrospectively from a propensity-score matched cohort including 42 STEMI patients (21 consecutive VF and 21 non-VF). Ultra-performance liquid chromatography and mass spectrometry in combination with a comprehensive analysis of metabolomic data using Metaboanalyst 5.0 version were performed. As a result, the retinal metabolism pathway proved to be the most discriminative for the VF phenotype. Furthermore, 9-cis-Retinoic acid (9cRA) and dehydrophytosphingosine proved to be the most discriminative biomarkers. Biomarker analysis through receiver operating characteristic (ROC) curve showed the 2-metabolite biomarker panel yielding an area under the curve (AUC) of 0.836. The model based on Monte Carlo cross-validation found that 9cRA had the greatest probability of appearing in the predictive panel of biomarkers in the model. Validation of model efficiency based on an ROC curve showed that the combination model constructed by 9cRA and dehydrophytosphingosine had a good predictive value for early-onset VF after STEMI, and the AUC was 0.884 (95% CI 0.714-1). Conclusively, the retinol metabolism pathway was the most powerful pathway for differentiating the post-STEMI VF phenotype. 9cRA was the most important predictive biomarker of VF, and a plasma biomarker panel made up of two metabolites, may help to build a potent predictive model for VF.

Serum uric acid level is associated with reperfusion ventricular arrhythmias in acute myocardial infarction.

BACKGROUND AND AIM: In the acute phase of acute myocardial infarction (AMI), reperfusion ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation (Reperfusion VT/VF) resulting from reperfusion injury are one of the causes of in-hospital death. Predicting Reperfusion VT/VF is clinically important. Previous studies have reported that oxidative stress is the cause of reperfusion injury and reperfusion arrhythmia. There are also reports that xanthine oxidase inhibitors have the effect of preventing reperfusion arrhythmia. We hypothesized that hyperuricemia is a risk factor for reperfusion arrhythmias in AMI. The aim of our study is to investigate whether serum uric acid is associated with Reperfusion VT/VF in acute myocardial infarction. METHOD: This is a single-center, retrospective cohort study. We enrolled 612 ST elevation myocardial infarction patients who underwent successful primary percutaneous coronary intervention (PCI). We divided patients into a high serum uric acid group (HUA group) and a low serum uric acid group (LUA group) with a cutoff value of 7.0 mg/dl, which is the standard value of serum uric acid. We compared the frequency of Reperfusion VT/VF in both groups. RESULT: There were 111 patients in the HUA group and 512 patients in the LUA group. Creatinine tended to be higher in the HUA group than in the LUA group. (1.12 ± 0.41 mg/dl VS 0.92 ± 1.10 mg/dl P = 0.06). The frequency of Reperfusion VT/VF was significantly higher in the HUA group than in the LUA group (17.1% VS 4.0% P < 0.001). CONCLUSION: Elevated serum uric acid is associated with higher frequency of reperfusion ventricular arrhythmia.

Prognostic value of admission serum magnesium in acute myocardial infarction complicated by malignant ventricular arrhythmias.

OBJECTIVES: Although electrolyte abnormalities are related to worse clinical outcomes in patients with acute myocardial infarction (AMI), little is known about the association between admission serum magnesium level and adverse events in AMI patients complicated by out-of-hospital cardiac arrest presenting with malignant ventricular arrhythmias (OHCA-MVA). We investigated the prognostic value of serum magnesium level on admission in these patients. METHODS: We retrospectively analyzed the data of 165 consecutive reperfused AMI patients complicated with OHCA-MVA between April 2007 and February 2020 in our university hospital. Serum magnesium concentration was measured on admission. The primary outcome was in-hospital death. RESULTS: Fifty-four patients (33%) died during hospitalization. Higher serum magnesium level was significantly related to in-hospital death (Fine & Gray's test; p < 0.001). In multivariable logistic regression analyses, serum magnesium level on admission was independently associated with in-hospital death (hazard ratio 2.68, 95% confidence interval 1.24-5.80) even after adjustment for covariates. Furthermore, the incidences of cardiogenic shock necessitating an intra-aortic balloon pump (p = 0.005) or extracorporeal membrane oxygenation (p < 0.001), tracheal intubation (p < 0.001) and persistent vegetative state (p = 0.002) were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level. CONCLUSIONS: In reperfused AMI patients complicated by OHCA-MVA, admission serum magnesium level might be a potential surrogate marker for predicting in-hospital death.

Effects of ω-3 PUFA and ascorbic acid combination on post-resuscitation myocardial function.

Accumulating evidence demonstrated that administration of ω-3 polyunsaturated fatty acid (ω-3 PUFA) or ascorbic acid (AA) following cardiac arrest (CA) improves survival. Therefore, we investigate the effects of ω-3 PUFA combined with AA on myocardial function after CA and cardiopulmonary resuscitation (CPR) in a rat model. Thirty male rats were randomized into 5 groups: (1) sham; (2) control; (3) ω-3 PUFA; (4) AA; (5) ω-3 PUFA + AA. Ventricular fibrillation (VF) was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Infusion of drug or vehicle occurred at the start of CPR. Myocardial function and sublingual microcirculation were measured at baseline and after return of spontaneous circulation (ROSC). Heart tissues and blood were collected 6 h after ROSC. Myocardial function and sublingual microcirculation improvements were seen with ω-3 PUFA or AA compared to control after ROSC (p < 0.05). ω-3 PUFA + AA shows a better myocardial function than ω-3 PUFA or AA (p < 0.05). ω-3 PUFA or AA decreases pro-inflammatory cytokines, cTnI, myocardium malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) modified proteins compared to control (p < 0.05). ω-3 PUFA and AA combined have lower MDA and 4-HNE modified proteins than alone (p < 0.05). ω-3 PUFA or AA treatment reduces the severity of post-resuscitation myocardial dysfunction, improves sublingual microcirculation, decreases lipid peroxidation and systemic inflammation in the early phase of recovery following CA and resuscitation. A combination of ω-3 PUFA and AA treatment confers an additive effect in suppressing lipid peroxidation and improving myocardial function.

Electrolyte Abnormalities in Patients Presenting With Ventricular Arrhythmia (from the LYTE-VT Study).

Electrolyte abnormalities are a known trigger for ventricular arrhythmia, and patients with heart disease on diuretic therapy may be at higher risk for electrolyte depletion. Our aim was to determine the prevalence of electrolyte depletion in patients presenting to the hospital with sustained ventricular tachycardia or ventricular fibrillation (VT/VF) versus heart failure, and identify risk factors for electrolyte depletion. Consecutive admissions to a tertiary care hospital for VT/VF were identified between July 2016 and October 2018 using the electronic medical record and compared with an equal number of consecutive admissions for heart failure (CHF). The study included 280 patients (140 patients in each group; mean age 63, 60% male, 59% African American). Average EF in the VT/VF and CHF groups was 30% and 33%, respectively. Hypokalemia (K < 3.5 mmol/L) and severe hypokalemia (K < 3.0 mmol/L) were present in 35.7% and 13.6%, respectively, of patients with VT/VF, compared to 12.9% and 2.7% of patients with CHF (p < 0.001 and p = 0.001, respectively, between groups). Hypomagnesemia was found in 7.8% and 5.8% of VT/VF and CHF patients, respectively (p = 0.46). Gastrointestinal illness and recent increases in diuretic dose were strongly associated with severe hypokalemia in VT/VF patients (odds ratio: 11.1 and 21.9, respectively; p < 0.001). In conclusion, hypokalemia is extremely common in patients presenting with VT/VF, much more so than in patients with CHF alone. Preceding gastrointestinal illness and increase in diuretic dose were strongly associated with severe hypokalemia in the VT/VF population, revealing a potential opportunity for early intervention and arrhythmia risk reduction.

Potassium Disturbances and Risk of Ventricular Fibrillation Among Patients With ST-Segment-Elevation Myocardial Infarction.

Background Potassium disturbances per se increase the risk of ventricular fibrillation (VF). Whether potassium disturbances in the acute phase of ST-segment-elevation myocardial infarction (STEMI) are associated with VF before primary percutaneous coronary intervention (PPCI) is uncertain. Methods and Results All consecutive STEMI patients were identified in the Eastern Danish Heart Registry from 1999 to 2016. Comorbidities and medication use were assessed from Danish nationwide registries. Potassium levels were collected immediately before PPCI start. Multivariate logistic models were performed to determine the association between potassium and VF. The main analysis included 8624 STEMI patients of whom 822 (9.5%) had VF before PPCI. Compared with 6693 (77.6%) patients with normokalemia (3.5-5.0 mmol/L), 1797 (20.8%) patients with hypokalemia (<3.5 mmol/L) were often women with fewer comorbidities, whereas 134 (1.6%) patients with hyperkalemia (>5.0 mmol/L) were older with more comorbidities. After adjustment, patients with hypokalemia and hyperkalemia had a higher risk of VF before PPCI (odds ratio 1.90, 95% CI 1.57-2.30, P<0.001) and (odds ratio 3.36, 95% CI 1.95-5.77, P<0.001) compared with normokalemia, respectively. Since the association may reflect a post-resuscitation phenomenon, a sensitivity analysis was performed including 7929 STEMI patients without VF before PPCI of whom 127 (1.6%) had VF during PPCI. Compared with normokalemia, patients with hypokalemia had a significant association with VF during PPCI (odds ratio 1.68, 95% CI 1.01-2.77, P=0.045) after adjustment. Conclusions Hypokalemia and hyperkalemia are associated with increased risk of VF before PPCI during STEMI. For hypokalemia, the association may be independent of the measurement of potassium before or after VF.

Growth differentiation factor-15 is a predictive biomarker in primary ventricular fibrillation: The RUTI-STEMI-PVF study.

BACKGROUND: Primary ventricular fibrillation is an ominous complication of ST-segment elevation myocardial infarction, and proper biomarkers for risk prediction are lacking. Growth differentiation factor-15 is a marker of inflammation, oxidative stress and hypoxia with well-established prognostic value in ST-segment elevation myocardial infarction patients. We explored the predictive value of growth differentiation factor-15 in a subgroup of ST-segment elevation myocardial infarction patients with primary ventricular fibrillation. METHODS: Prospective registry of ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention from February 2011-August 2015. Growth differentiation factor-15 concentrations were measured on admission. Logistic regression and Cox proportional regression analyses were used. RESULTS: A total of 1165 ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention (men 78.5%, age 62.3±13.1 years) and 72 patients with primary ventricular fibrillation (6.2%) were included. Compared to patients without primary ventricular fibrillation, median growth differentiation factor-15 concentration was two-fold higher in ST-segment elevation myocardial infarction patients with primary ventricular fibrillation (2655 vs 1367 pg/ml, p<0.001). At 30 days, mortality was 13.9% and 3.6% in patients with and without primary ventricular fibrillation, respectively (p<0.001), and median growth differentiation factor-15 concentration in patients with primary ventricular fibrillation was five-fold higher among those who died vs survivors (13,098 vs 2415 pg/ml, p<0.001). In a comprehensive multivariable analysis including age, sex, clinical variables, reperfusion time, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T, growth differentiation factor-15 remained an independent predictor of 30-day mortality, with odds ratios of 3.92 (95% confidence interval 1.35-11.39) in patients with primary ventricular fibrillation (p=0.012) and 1.72 (95% confidence interval 1.23-2.40) in patients without primary ventricular fibrillation (p=0.001). CONCLUSIONS: Growth differentiation factor-15 is a robust independent predictor of 30-day mortality in ST-segment elevation myocardial infarction patients with primary ventricular fibrillation.

Near-infrared spectroscopy after out-of-hospital cardiac arrest.

BACKGROUND: Cerebral hypoperfusion may aggravate neurological damage after cardiac arrest. Near-infrared spectroscopy (NIRS) provides information on cerebral oxygenation but its relevance during post-resuscitation care is undefined. We investigated whether cerebral oxygen saturation (rSO2) measured with NIRS correlates with the serum concentration of neuron-specific enolase (NSE), a marker of neurological injury, and with clinical outcome in out-of-hospital cardiac arrest (OHCA) patients. METHODS: We performed a post hoc analysis of a randomised clinical trial (COMACARE, NCT02698917) comparing two different levels of carbon dioxide, oxygen and arterial pressure after resuscitation from OHCA with ventricular fibrillation as the initial rhythm. We measured rSO2 in 118 OHCA patients with NIRS during the first 36 h of intensive care. We determined the NSE concentrations from serum samples at 48 h after cardiac arrest and assessed neurological outcome with the Cerebral Performance Category (CPC) scale at 6 months. We evaluated the association between rSO2 and serum NSE concentrations and the association between rSO2 and good (CPC 1-2) and poor (CPC 3-5) neurological outcome. RESULTS: The median (inter-quartile range (IQR)) NSE concentration at 48 h was 17.5 (13.4-25.0) µg/l in patients with good neurological outcome and 35.2 (22.6-95.8) µg/l in those with poor outcome, p < 0.001. We found no significant correlation between median rSO2 and NSE at 48 h, rs = - 0.08, p = 0.392. The median (IQR) rSO2 during the first 36 h of intensive care was 70.0% (63.5-77.0%) in patients with good outcome and 71.8% (63.3-74.0%) in patients with poor outcome, p = 0.943. There was no significant association between rSO2 over time and neurological outcome. In a binary logistic regression model, rSO2 was not a statistically significant predictor of good neurological outcome (odds ratio 0.99, 95% confidence interval 0.94-1.04, p = 0.635). CONCLUSIONS: We found no association between cerebral oxygenation measured with NIRS and NSE concentrations or outcome in patients resuscitated from OHCA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02698917 . Registered on 26 January 2016.

In-Hospital Electrical Storm in Acute Myocardial Infarction　- Clinical Background and Mechanism of the Electrical Instability.

BACKGROUND: Recurrent ventricular tachycardia (VT) and fibrillation (VF), the so-called "electrical storm" (ES) occurs at various stages of acute myocardial infarction (AMI), but its incidence, background, and short-term prognosis remain unclear. Methods and Results: A retrospective observational study was performed using the registry database of the Tokyo CCU Network. The individual data of 6,003 patients with AMI during 2011-2012 was corrected. ES was defined as more than 3 episodes of sustained VT/VF during a 24-h period as first documented after hospitalization. ES occurred in 55 patients after admission (0.9%). The ES(+) group had more severe heart failure (Killip class >III), more extensive MI (peak-CK), greater inflammatory reaction (CRP), history of diabetes, and more frequent application of hemodialysis as compared with the ES(-) group (n=5,865). When the ES patients were divided into Early-ES (n=37: ES occurred ≤48 h after the onset of MI) and Late-ES (n=15 >48 h after onset of MI) groups, logistic regression analysis revealed that Early-ES was associated with severity of MI, whereas Late-ES was related to systemic disorders, including inflammation, renal dysfunction, or diabetes. Late-ES was an independent predictor of in-hospital death. CONCLUSIONS: In-hospital ES was a rare clinical manifestation of AMI. The features and background of the ES varied as time elapsed after admission for MI.

Serum potassium levels and outcomes in critically ill patients in the medical intensive care unit.

Objective To compare the outcomes of patients with and without a mean serum potassium (K+) level within the recommended range (3.5-4.5 mEq/L). Methods This prospective cohort study involved patients admitted to the medical intensive care unit (ICU) of Siriraj Hospital from May 2012 to February 2013. The patients' baseline characteristics, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, serum K+ level, and hospital outcomes were recorded. Patients with a mean K+ level of 3.5 to 4.5 mEq/L and with all individual K+ values of 3.0 to 5.0 mEq/L were allocated to the normal K+ group. The remaining patients were allocated to the abnormal K+ group. Results In total, 160 patients were included. Their mean age was 59.3±18.3 years, and their mean APACHE II score was 21.8±14.0. The normal K+ group comprised 74 (46.3%) patients. The abnormal K+ group had a significantly higher mean APACHE II score, proportion of coronary artery disease, and rate of vasopressor treatment. An abnormal serum K+ level was associated with significantly higher ICU mortality and incidence of ventricular fibrillation. Conclusion Critically ill patients with abnormal K+ levels had a higher incidence of ventricular arrhythmia and ICU mortality than patients with normal K+ levels.

Renal denervation decreases susceptibility of the heart to ventricular fibrillation in a canine model of chronic kidney disease.

NEW FINDINGS: What is the central question of this study? Renal denervation (RDN) has been shown to be effective and safe, resulting in better control of blood pressure and an improvement in left ventricular hypertrophy in chronic kidney disease (CKD) patients. Ventricular arrhythmias and sudden cardiac death are common causes of death in CKD patients, but previous studies pay almost no attention to the effects of RDN on the risk of ventricular fibrillation associated with CKD. What is the main finding and its importance? Renal denervation could decrease susceptibility of the heart to ventricular fibrillation in a canine CKD model. Improvement of left ventricular hypertrophy, sympathetic activation and inflammation by RDN may be responsible for its beneficial effects. Renal denervation (RDN) has been shown to have therapeutic value in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether RDN could decrease the susceptibility of the heart to ventricular fibrillation in a canine model of CKD. Twenty-one dogs were used. Chronic kidney disease was produced by subtotal nephrectomy in 16 dogs with RDN treatment (CKD + RDN group, n = 8) or sham RDN (CKD group, n = 8). Another five dogs underwent sham operation and sham RDN to serve as controls (CTR group). Parameters of renal function, blood pressure, echocardiography, ECG, noradrenaline and inflammation were measured at baseline and 6 weeks after the surgical procedure. The ventricular fibrillation threshold (VFT) was determined at the end of the study. Subtotal nephrectomy successfully induced a canine CKD model. When compared with the CTR group, subtotal nephrectomy in the CKD group significantly elevated blood pressure; increased the left ventricular mass, end-diastolic left ventricular internal dimension, left ventricular end-diastolic posterior wall thickness and end-diastolic interventricular septum thickness; prolonged the QT interval, corrected QT interval, the interval from the peak to the end of the T wave (Tp-e) and the corrected Tp-e interval; and increased the QT dispersion and the Tp-e/QT ratio; decreased the VFT; and increased the serum concentrations of noradrenaline, C-reactive protein and interleukin-6. Renal denervation significantly attenuated these changes induced by CKD. The study demonstrated that RDN could decrease the susceptibility of the heart to ventricular fibrillation in this CKD model. Improvement of left ventricular hypertrophy, sympathetic activation and inflammation by RDN may be responsible for its beneficial effects.

Galectin-3 correlates with arrhythmogenic right ventricular cardiomyopathy and predicts the risk of ventricular -arrhythmias in patients with implantable defibrillators.

Background Arrhythmogenic right ventricular dysplasia (ARVD) is a heritable disorder characterized by fibro-fatty replacement of right ventricular myocytes, increased risk of ventricular arrhythmias, and sudden cardiac death. Galectin-3 (GAL3) is known to play an important role in a number of fibrotic conditions, including cardiac fibrosis. Many studies have focused on the association between GAL3 levels and cardiac fibrosis in heart failure. However, the role of GAL3 in the pathogenesis of ARVD and ventricular arrhythmias has not yet been evaluated thoroughly. The aim of this study was to explore GAL3 levels in patients with ARVD and its association with ventricular arrhythmias. Methods Twenty-nine patients with ARVD and 24 controls were included. All patients with ARVD had an implantable cardiac defibrillator (ICD) for primary or secondary prevention. Ventricular arrhythmia history was obtained from a chart review and ICD data interrogation. Galectin-3 levels were measured using an enzyme-linked immunosorbent assay. Results Patients with ARVD had higher plasma GAL3 levels (16.9 ± 2.6 ng/mL vs 11.3 ± 1.8 ng/mL, P < 0.001) than the control group. Ten patients had sustained or non-sustained ventricular arrhythmias during follow-up. In the multivariable analysis, left ventricular disease involvement (HR: 1.05; 95% CI: [1.01-1.12]; P = 0.03); functional capacity >2 (HR: 1.21; 95% CI: [1.13-1.31]; P < 0.005); and GAL3 levels (HR: 1.05; 95% CI: [1.00-1.11]; P = 0.01) independently predicted VT/VF. Conclusion We demonstrated that serum GAL3 was significantly elevated in patients with ARVD. Also, serum GAL 3 levels could be regarded as a candidate biomarker in the diagnosis of ARVD which needs to be tested in larger prospective studies. In addition, GAL3 levels were higher in patients with VT/VF as compared with those without VT/VF.

The impact of serum potassium-influencing antihypertensive drugs on the risk of out-of-hospital cardiac arrest: A case-control study.

AIMS: Sudden cardiac arrest (SCA) is a complex multifactorial event and most commonly caused by ventricular tachycardia/ fibrillation (VT/ VF). Some antihypertensive drugs could induce hypokalaemia or hyperkalaemia, which may increase susceptibility to VT/VF and SCA. OBJECTIVE: To assess the association between different classes of antihypertensive drugs classified according to their potential impact on serum potassium levels and the occurrence of out-of-hospital cardiac arrest (OHCA) based on VT/VF. METHODS: A case-control study was performed among current users of antihypertensive drugs. Cases were OHCA victims with electrocardiogram documented VT/VF drawn from the AmsteRdam REsuscitation STudies (ARREST) registry, and controls were non-OHCA individuals from the PHARMO database. Antihypertensive drugs were classified into: (i) antihypertensives with neutral effect on serum potassium levels; (ii) hypokalaemia-inducing antihypertensives; (iii) hyperkalaemia-inducing antihypertensives; (iv) combination of antihypertensives with hypo- and hyperkalaemic effects. RESULTS: We included 1345 cases and 4145 controls. The risk of OHCA was significantly increased among users of hypokalaemia-inducing antihypertensives [adjusted odds ratio (OR) 1.39; 95% confidence interval (CI) 1.10-1.76] and among users of a combination of antihypertensives with hypo- and hyperkalaemic effects (adjusted OR 1.42; 95%CI 1.17-1.72) vs. users of antihypertensives with neutral effect. There was no difference in OHCA risk between users of hyperkalaemia-inducing antihypertensives vs. users of antihypertensive drugs with neutral effect (adjusted OR 1.15; 95%CI 0.95-1.40). CONCLUSION: The risk of OHCA is significantly increased in patients who were current users of hypokalaemia-inducing antihypertensives and patients using a combination of antihypertensives with hypo- and hyperkalaemic effects.

Cerebral Hemodynamics and Metabolism During Cardiac Arrest and Cardiopulmonary Resuscitation Using Hyperspectral Near Infrared Spectroscopy.

BACKGROUND: Maintaining cerebral oxygen delivery and metabolism during cardiac arrest (CA) through resuscitation is essential to improve the survival rate while avoiding brain injury. The effect of CA and cardiopulmonary resuscitation (CPR) on cerebral and muscle oxygen delivery and metabolism is not clearly quantified.Methods and Results:A novel hyperspectral near-infrared spectroscopy (hNIRS) technique was developed and evaluated to measure cerebral oxygen delivery and aerobic metabolism during ventricular fibrillation (VF) CA and CPR in 14 pigs. The hNIRS parameters were measured simultaneously on the dura and skull to investigate the validity of non-invasive hNIRS measurements. In addition, we compared the hNIRS data collected simultaneously on the brain and muscle. Following VF induction, oxygenated hemoglobin (HbO2) declined with a 9.9 s delay and then cytochrome-c-oxidase (Cyt-ox) decreased on average 4.4 s later (P<0.05). CPR improved cerebral metabolism, which was reflected by an average 0.4 µmol/L increase in Cyt-ox, but had no significant effect on HbO2, deoxygenated hemoglobin (HHb) and tissue oxygen saturation (tSO2). Cyt-ox had greater correlation with HHb than HbO2. Muscle metabolism during VF and CPR was significantly different from that of the brain. The total hemoglobin concentration (in the brain only) increased after ~200 s of untreated CA, which is most likely driven by cerebral autoregulation through vasodilation. CONCLUSIONS: Overall, hNIRS showed consistent measurements of hemodynamics and metabolism during CA and CPR.

ß1 -Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea-pigs.

NEW FINDINGS: What is the central question of this study? High titres of autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AAs) can be detected in the sera of patients with ventricular arrhythmias, but a causal relationship between ß1 -AAs and ventricular arrhythmias has not been established. What is the main finding and its importance? Monoclonal ß1 -AAs (ß1 -AR mAbs) were used in the experiments. We showed that ß1 -AR mAbs increased susceptibility to ventricular arrhythmias and induced repolarization abnormalities. Antibody adsorption of ß1 -AAs will be a potential new therapeutic strategy for ventricular arrhythmias in patients with high titres of ß1 -AAs. High titres of autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AAs) can be detected in sera from patients with ventricular arrhythmias, but a causal relationship between ß1 -AAs and ventricular arrhythmias has not been established. In this work, ECGs of guinea-pigs and isolated guinea-pig hearts were recorded. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were evoked by programmed electrical stimulation of the left ventricular epicardium of isolated guinea-pig hearts. The monophasic action potential and effective refractory period of the left ventricle were recorded in paced isolated guinea-pig hearts. Furthermore, to increase the specificity, monoclonal autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AR mAbs) were used in all experiments. The results showed that ß1 -AR mAbs induced premature ventricular contractions in guinea-pigs and isolated guinea-pig hearts. In addition, ß1 -AR mAbs decreased the threshold of VT/VF and prolonged the duration of VT/VF. Furthermore, ß1 -AR mAbs shortened the corrected QT interval and effective refractory period, and prolonged late-phase repolarization of the monophasic action potential (MAPD90-30 ). These changes in electrophysiological parameters might be attributed, at least in part, to the arrhythmogenicity of ß1 -AR mAbs.

Does therapeutic hypothermia during extracorporeal cardiopulmonary resuscitation preserve cardiac function?

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (E-CPR) is increasingly used as a rescue method in the management of cardiac arrest and provides the opportunity to rapidly induce therapeutic hypothermia. The survival after a cardiac arrest is related to post-arrest cardiac function, and the application of therapeutic hypothermia post-arrest is hypothesized to improve cardiac outcome. The present animal study compares normothermic and hypothermic E-CPR considering resuscitation success, post-arrest left ventricular function and magnitude of myocardial injury. METHODS: After a 15-min untreated ventricular fibrillation, the pigs (n = 20) were randomized to either normothermic (38 °C) or hypothermic (32-33 °C) E-CPR. Defibrillation terminated ventricular fibrillation after 5 min of E-CPR, and extracorporeal support continued for 2 h, followed by warming, weaning and a stabilization period. Magnetic resonance imaging and left ventricle pressure measurements were used to assess left ventricular function pre-arrest and 5 h post-arrest. Myocardial injury was estimated by serum concentrations of cardiac TroponinT and Aspartate transaminase (ASAT). RESULTS: E-CPR resuscitated all animals and the hypothermic strategy induced therapeutic hypothermia within minutes without impairment of the resuscitation success rate. All animals suffered a severe global systolic left ventricular dysfunction post-arrest with 50-70% reductions in stroke volume, ejection fraction, wall thickening, strain and mitral annular plane systolic excursion. Serum concentrations of cardiac TroponinT and ASAT increased considerably post-arrest. No significant differences were found between the two groups. CONCLUSIONS: Two-hour therapeutic hypothermia during E-CPR offers an equal resuscitation success rate, but does not preserve the post-arrest cardiac function nor reduce the magnitude of myocardial injury, compared to normothermic E-CPR. Trial registration FOTS 4611/13 registered 25 October 2012.

High Serum Tumor Necrosis Factor Levels in the Early Post-Cardiac Arrest Period Are Associated with Poor Short-Term Survival in a Swine Model of Ventricular Fibrillation.

Most resuscitated victims of out-of-hospital cardiac arrest who survive to hospital expire due to the postresuscitation syndrome. This syndrome is characterized by a sepsis-like proinflammatory state. The objective of this investigation was to determine whether a relationship exists between the rise of tumor necrosis factor (TNF), a proinflammatory cytokine, following return of spontaneous circulation (ROSC), and early postarrest survival in a clinically relevant animal model of spontaneous ventricular fibrillation (VF). Mixed-breed Yorkshire swine (n = 20), weighing 39 ± 5 kg, were anesthetized and catheters placed in the right atrium and left ventricle/ascending aorta for continuous pressure monitoring. VF was induced by occluding the left anterior descending coronary artery with an angioplasty balloon. After 7 min of untreated VF, advanced life support resuscitation attempts were made for up to 20 min. Animals achieving ROSC were monitored for 3 h and fluid and pressor support was administered as needed. TNF levels were measured before VF and at 0, 15, and 30 min after ROSC using quantitative sandwich enzyme-linked immunosorbent assay. Twelve (60%) animals experienced early death, expiring during the 3 hour postarrest period (9 pulseless electrical activity, 2 VF, and 1 asystole). The TNF level at 15 min post-ROSC was significantly associated with death within the first 3 h post-ROSC with a univariate odds ratio of 1.4 [95% confidence interval (CI) 1.05-2.2, P = 0.01]. Using a cutoff TNF level of 525 pg/mL at 15 min post-ROSC had 100% negative predictive value (95% CI 0%-37%) and 67% positive predictive value (95% CI 35%-90%) for early death with a hazard ratio of 6.6 (95% CI 1.9-23.5). TNF increases shortly after ROSC and is predictive of early death. Early identification of resuscitated victims at greatest risk for hemodynamic collapse and recurrent arrest might facilitate the use of early hospital-based interventions to decrease the likelihood of a poor outcome.

Inflammation markers are associated with metabolic syndrome and ventricular arrhythmia in patients with coronary artery disease.

BACKGROUND: Inflammation plays a major role in the development and progression of atherosclerosis and coronary artery disease (CAD). Inflammation markers, including white blood cell (WBC) count, C-reactive protein (CRP) and interleukin-6 (IL-6), are widely used for cardiovascular risk prediction. The aim of the study was to establish factors associated with WBC, CRP and IL-6 in patients with CAD. Two functional polymorphisms in genes encoding enzymes participating in adenosine metabolism were analyzed (C34T AMPD1, G22A ADA). METHODS: Plasma concentrations of IL-6 were measured using high-sensitivity ELISA kits, and the nephelometric method was used for high-sensitivity CRP (hs-CRP) measurement in 167 CAD patients. RESULTS: Presence of metabolic syndrome (MS) and its components, presence of heart failure, severity of CAD symptoms, severe past ventricular arrhythmia (sustained ventricular tachycardia [sVT] or ventricular fibrillation [VF]), lower left ventricle ejection fraction, higher left ventricle mass index, higher end-diastolic volume and higher number of smoking pack-years were significantly associated with higher WBC, CRP and IL-6. Strong associations with arrhythmia were observed for IL-6 (median 3.90 vs 1.89 pg/mL, p<0.00001) and CRP concentration (6.32 vs 1.47 mg/L, p=0.00009), while MS was associated most strongly with IL-6. CRP and IL-6 were independent markers discriminating patients with sVT or VF. There were no associations between AMPD1 or ADA genotypes and inflammation markers. CONCLUSIONS: WBC, CRP and IL-6 are strongly associated with components of the metabolic syndrome. Their strong association with life-threatening ventricular arrhythmia emphasizes the proarrhythmic role of inflammation in the increased cardiovascular risk of CAD patients.