Explainable Prediction Model of the Need for Emergency Hemostasis Using Field Information During Physician-Staffed Helicopter Emergency Medical Service Interventions: A Single-Center, Retrospective, Observational Pilot Study.

OBJECTIVE: Early recognition of hemostasis is important to prevent trauma-related deaths. We conducted a pilot study of a predictive model of hemostatic need using factors that can be collected during helicopter emergency medical service (HEMS) interventions until transport hospital selection using cases from our institution. METHODS: This single-center, retrospective, observational pilot study included 251 trauma patients aged ≥ 18 years treated with HEMS between April 2017 and March 2022, in Nara Medical University. Cardiac arrest and pre-HEMS treatment patients were excluded. Emergency hemostatic surgery prediction models were constructed using the light gradient boosting machine cross-validation method using objective data that could be collected before hospital determination. The accuracy of this model was compared with that of the ground emergency medical service-based model, and factors influencing outcome were visualized using Shapley additive explanations. RESULTS: The predictive accuracy of the model with HEMS intervention factors was an area under the receiver operating characteristic curve of 0.80, superior to the 0.73 accuracy area under the receiver operating characteristic curve for ground emergency medical services constructed with contact information. Clinically important factors, such as shock index, blood pressure changes, and ultrasound findings, had a significant impact on outcomes, with nonmonotonic effects observed across factors. CONCLUSION: This pilot study suggests that predictive models of emergency hemostasis can be built using limited prehospital information. To validate this model, a larger, multicenter study is recommended.

Cell-free DNA Release in the Plasma of Patients with Cardiac Disease is Associated with Cell Death Processes.

Cell-free DNA (cfDNA) is released into the plasma of patients with cardiac disease. Here, the source and mechanism of plasma cfDNA release in patients with myocardial infarction (MI) and other cardiac diseases (n = 59) were investigated. Plasma levels of various markers including M30 (apoptosis), M65 (apoptosis and necrosis), cyclophilin A (CyPA) (necrosis), and myeloperoxidase (MPO) (neutrophil activation) were assayed. The plasma cfDNA concentrations in MI and other cardiac diseases were significantly higher than that in the healthy control subjects. Significant differences were not observed among the cardiac disease patients (MI and other cardiac diseases) and healthy control subjects in M30, M65, and CyPA levels. In contrast,the MPO levels were significantly elevated in cardiac disease patients when compared to control groups, and MPO levels in MI patients were significantly higher than other cardiac diseases patients. These results suggest that cfDNA is mainly released by neutrophils via NETosis in addition to apoptosis except for epithelial apoptosis in patients with cardiac disease and the degree is greater in MI patients. The results from this study provide basic information for diagnosis marker of MI.

Increased plasma glutamate in non-smokers with vasospastic angina pectoris is associated with plasma cystine and antioxidant capacity.

Objectives. Endothelial dysfunction caused by oxidative stress plays an important role in the development of vasospastic angina pectoris (VSAP). Glutamate causes endothelial dysfunction by generating oxidative stress, and it inhibits cystine import into endothelial cells via the cystine/glutamate antiporter (XC-), which leads to depletion of antioxidant glutathione. However, whether glutamate and cystine are implicated in the pathogenesis of VSAP remains unclear. We investigated plasma glutamate and cystine levels, oxidative stress markers and antioxidant capacity in non-smoker patients with VSAP to determine whether glutamate and cystine are associated with the development of VSAP. We assessed 49 non-smokers assigned to groups with (n = 27) and without (n = 22) VSAP, and also measured plasma glutamate, cystine, nitrotyrosine, reactive oxygen metabolites and biological antioxidant potential. Results. Plasma glutamate and cystine values were significantly higher in the group with, than without VSAP (59.8 ± 25.7 vs. 43.5 ± 18.7 µmol/L, p = .016 and 35.3 ± 14.2 vs. 25.2 ± 9.1 µmol/L, p = .0056, respectively). Plasma glutamate and cystine values were significantly and positively associated (r = 0.32, p = .027). Levels of the oxidative stress markers nitrotyrosine and reactive oxygen metabolites, and biological antioxidant potential of as a measure of antioxidant capacity, did not significantly differ between the two groups. However, glutamate and biological antioxidant potential values were significantly and negatively associated (r = -0.3, p = .036). Conclusion. Plasma glutamate levels were increased in patients with VSAP who did not smoke, and they were positively associated with plasma cystine and negatively associated with the biological antioxidant potential levels.

Glyceraldehyde-derived advanced glycation end-products are associated with left ventricular ejection fraction and brain natriuretic peptide in patients with diabetic adverse cardiac remodeling.

Objectives: Glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) have a strong binding affinity for their cognate receptor and elicit oxidative stress and inflammation. However, it remains unknown whether the levels of Glycer-AGEs correlate with the severity of cardiac function and heart failure in patients with diabetic adverse cardiac remodeling (DbCR). Fourteen heart failure patients with type 2 diabetes mellitus (DM) without other cardiac disorders (DbCR group) were enrolled. Another 14 patients with idiopathic dilated cardiomyopathy (DCM) without DM were served as a control (DCM group). All patients were assessed for serum Glycer-AGEs, nitrotyrosine (NT), and tumor necrosis factor alpha (TNFα) and for plasma brain natriuretic peptide (BNP). The left ventricular ejection fraction (LVEF) was evaluated by echocardiography. Results: The mean serum levels of Glycer-AGEs, NT, and TNFα in the DbCR group were significantly higher than those in the DCM group (for Glycer-AGEs, p = .0073; for NT, p = .005; for TNFα, p < .0001, respectively). In the patients with DbCR, the levels of serum Glycer-AGEs and TNFα were closely associated with LVEF and BNP values. Conclusions: Both Glycer-AGEs and TNFα showed close associations with LVEF and the levels of BNP in patients with DbCR. Glycer-AGEs and TNFα may play a pathological role in the development of DbCR.

Rapid DNA Sequencing Technology Based on the Sanger Method for Bacterial Identification.

Antimicrobial resistance, a global health concern, has been increasing due to inappropriate use of antibacterial agents. To facilitate early treatment of sepsis, rapid bacterial identification is imperative to determine appropriate antibacterial agent for better therapeutic outcomes. In this study, we developed a rapid PCR method, rapid cycle sequencing, and microchip electrophoresis, which are the three elemental technologies for DNA sequencing based on the Sanger sequencing method, for bacterial identification. We achieved PCR amplification within 13 min and cycle sequencing within 14 min using a rapid thermal cycle system applying microfluidic technology. Furthermore, DNA analysis was completed in 14 min by constructing an algorithm for analyzing and performing microchip electrophoresis. Thus, the three elemental Sanger-based DNA sequencing steps were accomplished within 41 min. Development of a rapid purification process subsequent to PCR and cycle sequence using a microchip would help realize the identification of causative bacterial agents within one hour, and facilitate early treatment of sepsis.

Factors associated with EMS on-scene time and its regional difference in road traffic injuries: a population-based observational study.

BACKGROUND: The outcome of road traffic injury (RTI) is determined by duration of prehospital time, patient's demographics, and the type of injury and its mechanism. During the emergency medical service (EMS) prehospital time interval, on-scene time should be minimized for early treatment. This study aimed to examine the factors influencing on-scene EMS time among RTI patients. METHODS: We evaluated 19,141 cases of traffic trauma recorded between April 2014 and March 2020 in the EMS database of the Nara Wide Area Fire Department and the prehospital database of the emergency Medical Alliance for Total Coordination of Healthcare (e-MATCH). To examine the association of the number of EMS phone calls until hospital acceptance, age ≥65 years, high-risk injury, vital signs, holiday, and nighttime (0:00-8:00) with on-scene time, a generalized linear mixed model with random effects for four study regions was conducted. RESULTS: EMS phone calls were the biggest factor, accounting for 5.69 minutes per call, and high-risk injury accounted for an additional 2.78 minutes. Holiday, nighttime, and age ≥65 years were also associated with increased on-scene time, but there were no significant vital sign variables for on-scene time, except for the level of consciousness. Regional differences were also noted based on random effects, with a maximum difference of 2 minutes among regions. CONCLUSIONS: The number of EMS phone calls until hospital acceptance was the most significant influencing factor in reducing on-scene time, and high-risk injury accounted for up to an additional 2.78 minutes. Considering these factors, including regional differences, can help improve the regional EMS policies and outcomes of RTI patients.

Comparison of Changes in Vital Signs During Ground and Helicopter Emergency Medical Services and Hospital Interventions.

OBJECTIVE: Few studies have evaluated the effects of helicopter emergency medical services (HEMS) alone. This single-center study compared the changes in vital signs during ground emergency medical services (GEMS), HEMS, and hospital interventions to assess the impact of HEMS interventions. METHODS: This retrospective observational study included 168 trauma patients older than 18 years of age who received HEMS. Patients with cardiac arrest or those who received medical attention before HEMS were excluded. We assessed 3 intervention phases (GEMS, HEMS, and hospital). The changes in heart rate, systolic blood pressure, respiratory rate, and shock index in response to interventions were calculated and divided by the intervention time, and the changes observed during the interventions were compared. RESULTS: No changes in vital signs were observed when receiving GEMS. Systolic blood pressure increased and shock index decreased after HEMS, whereas systolic blood pressure decreased and shock index increased during hospital interventions. Heart rate showed no significant change (P = .12), and respiratory rate showed very little change. Systolic blood pressure increased significantly during HEMS compared with the pre- and postintervention periods. CONCLUSION: Changes in vital signs differed according to the intervention. Systolic blood pressure increased during HEMS but not with GEMS or hospital interventions.

Monitoring the roles of prothrombin activation fragment 1 and 2 (F1 + 2) in patients with atrial fibrillation receiving rivaroxaban and apixaban.

Factor Xa (FXa) inhibitors are recommended for use in fixed doses without laboratory monitoring. However, prior studies reported the importance of establishing biomarkers representing anticoagulation intensity related to bleeding or thrombotic events. To test the hypothesis that prothrombin activation fragment 1 and 2 (F1 + 2), a non-specific marker of thrombin generation, could be altered during FXa inhibitor treatment in patients with atrial fibrillation. We conducted the study in two different clinical settings. First, the interrelations among biomarkers representing coagulation/fibrinolysis were investigated in 80 patients in an outpatient clinic. Second, these biomarkers were evaluated in 75 patients who underwent radiofrequency catheter ablation. Plasma concentration of FXa inhibitors was evaluated using an anti-FXa chromogenic assay (C-Xa). In the outpatient study, only F1 + 2 exhibited a significant and negative association with C-Xa (rS = - 0.315, p = 0.026), and 37% of the variance could be explained by C-Xa levels. F1 + 2 levels above the reference range (> 229 pmol/L) could be considered as a cut-off to identify poor patient compliance or under-dosing. In the peri-ablation study, increased F1 + 2 levels were associated with decline of C-Xa levels after periprocedural discontinuation of FXa inhibitors, which was greater in the rivaroxaban group than in the apixaban group. F1 + 2 showed modest and inverse association with plasma concentration of rivaroxaban and apixaban in patients with atrial fibrillation. Larger study to test the hypothesis that continued thrombin generation despite anticoagulation is associated with a heightened risk of clinical events is required.

Abnormal breathing of sudden cardiac arrest victims described by laypersons and its association with emergency medical service dispatcher-assisted cardiopulmonary resuscitation instruction.

BACKGROUND: Current guidelines for cardiopulmonary resuscitation (CPR) emphasise that emergency medical service (EMS) dispatchers should identify sudden cardiac arrest (CA) with abnormal breathing and assist lay rescuers performing CPR. However, lay rescuers description of abnormal breathing may be inconsistent, and it is unclear how EMS dispatchers provide instruction for CPR based on the breathing status of the CA victims described by laypersons. METHODS AND RESULTS: To investigate the incidence of abnormal breathing and the association between the EMS dispatcher-assisted CPR instruction and layperson CPR, we retrospectively analysed 283 witnessed CA cases whose information regarding breathing status of CA victims was available from population-based prospective cohort data. In 169 cases (59.7%), laypersons described that the CA victims were breathing in various ways, and that the victims were 'not breathing' in 114 cases (40.3%). Victims described as breathing in various ways were provided EMS dispatch-instruction for CPR less frequently than victims described as 'not breathing' (27.8% (47/169) vs 84.2% (96/114); p<0.001). Multivariate logistic regression showed that EMS dispatch-instruction for CPR was associated significantly with layperson CPR (adjusted OR, 11.0; 95% CI, 5.72 to 21.2). CONCLUSIONS: This population-based study indicates that 60% of CA victims showed agonal respiration, which was described as breathing in various ways at the time of EMS call. Although EMS dispatch-instruction was associated significantly with an increase in layperson CPR, abnormal breathing was associated with a much lower rate of CPR instruction and, in turn, was related to a much lower rate of bystander CPR.

Chk1-mediated phosphorylation of receptor-associated late transducer at serine 250 increases its stability by stimulating its interaction with 14-3-3.

Receptor-associated late transducer (RALT) acts as a negative feedback inhibitor of ErbB receptor signaling via physical interaction with ErbB. Although RALT contains a 14-3-3 binding motif (247-RSHSGP-252), little is known about the molecular basis and significance of binding to 14-3-3. Here, we report that 14-3-3 interacts with RALT in H9c2 and COS-7 cells in a Ser-250 phosphorylation-dependent manner. An in vitro kinase assay showed that RALT is a substrate for checkpoint kinase 1 (Chk1). Interaction between ectopically expressed RALT and endogenous 14-3-3 was partially suppressed by pretreatment with the Chk1 inhibitor, UCN-01. In addition, expression of constitutively active Chk1 (Chk11-365 ) resulted in increased phosphorylation of the RALT 14-3-3 binding motif and enhanced the interaction between RALT and 14-3-3θ. Furthermore, fluorescence microscopy revealed that rapid trafficking of RALT to endosome-like vesicle structures was decelerated by coexpression of Chk11-365 , whereas this coexpression had no significant impact on trafficking of the RALT S250A mutant. Finally, a cycloheximide chase assay indicated that coexpression of Chk11-365 decelerated the degradation of ectopically expressed RALT, but not that of the S250A mutant. Collectively, these results suggest that Chk1 plays a role in regulating RALT protein stability by facilitating the interaction between 14-3-3 and RALT.

Nutri-pharmacogenomics of warfarin anticoagulation therapy: VKORC1 genotype-dependent influence of dietary vitamin K intake.

Warfarin is the most widely prescribed oral anticoagulant, but large interindividual variations exist in the dose required to achieve comparable therapeutic effects. Several clinical and genetic variables have been identified that influence warfarin dosing. However, interactions between genotype and nutrition remain uncertain in terms of dietary vitamin K intake. To investigate genotype-nutrient interactions in warfarin anticoagulation therapy, 202 consecutive outpatients (M/F = 142/60, mean age, 69 years) undergoing treatment with warfarin were enrolled. Prevalent single nucleotide polymorphisms in VKORC1 and CYP2C9 were genotyped, and dietary vitamin K intake during the week preceding the blood sampling was quantitatively estimated by a dietitian-assisted questionnaire. Patients were classified according to low, medium, or high vitamin K intake. The mean daily warfarin dose in subjects with a VKORC1-1639 A/A genotype was significantly smaller than that with a -1639A/G genotype (2.74 vs. 3.91 mg/day, respectively, p < 0.0001). Dose requirements did not differ between subjects with a CYP2C9 *1/*3 genotype versus a CYP2C9 *1/*1 genotype. In subjects with a variant VKORC1-1639 G allele, the mean daily warfarin dose was significantly attenuated by low vitamin K intake compared with medium and high intake after adjustment for covariates (3.4 vs. 5.0 vs. 4.0 mg/day, respectively, p = 0.028). No such genotype effects were observed in homozygous patients for the VKORC1-1639 A allele. The results of the present study suggest that the capacity of dietary vitamin K intake to influence warfarin dose requirements during anticoagulation therapy is VKORC1 genotype-dependent, at least in part.

Identification of sepsis-causing bacteria from whole blood without culture using primers with no cross-reactivity to human DNA.

Sepsis is a major health concern globally, and identification of the causative organism usually takes several days. Furthermore, molecular amplification using whole blood from patients with sepsis remains challenging because of primer cross-reactivity with human DNA, which can delay appropriate clinical intervention. To address these concerns, we designed primers that could reduce cross-reactivity. By evaluating these primers against human DNA, we confirmed that the cross-reactivity observed with conventional primers was notably absent. In silico PCR further demonstrated the specificity and efficiency of the designed primers across 23 bacterial species that are often associated with sepsis. When tested using blood samples from sepsis patients, the designed primers showed moderate sensitivity and high specificity. Surprisingly, our method identified bacteria even in samples that were detected at other sites but tested negative using conventional blood culture methods. Although we identified some challenges, such as contamination with Acetobacter aceti due to the saponin pretreatment of samples, the developed method demonstrates remarkable potential for rapid identification of the causative organisms of sepsis and provides a new avenue for diagnosis in clinical practice.

Thrombotic Microangiopathy after a 15-year Treatment with Interferon Beta-1b in a Patient with Multiple Sclerosis: A Case Report and Review of Literature.

A 54-year-old woman with multiple sclerosis treated with interferon-ß (IFN-ß)-1b for 15 years presented with sustained hypertension (240/124 mmHg) and retinal bleeding. She had proteinuria, anemia, thrombocytopenia, elevated serum creatinine levels, and haptoglobin depletion. Intravenous nicardipine stabilized her blood pressure, but her renal function and platelet count deteriorated. The initial disintegrin-like metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13) activity was 28% of normal without its inhibitor. The subsequent peripheral appearance of schistocytes suggested thrombotic microangiopathy (TMA). After IFN-ß-1b cessation, the platelet count increased, and the blood pressure stabilized. The ADAMTS13 activity normalized, although the creatinine level did not. TMA may develop after the long-term use of IFN-ß without adverse events.

Explainable artificial intelligence-based prediction of poor neurological outcome from head computed tomography in the immediate post-resuscitation phase.

Predicting poor neurological outcomes after resuscitation is important for planning treatment strategies. We constructed an explainable artificial intelligence-based prognostic model using head computed tomography (CT) scans taken immediately within 3 h of resuscitation from cardiac arrest and compared its predictive accuracy with that of previous methods using gray-to-white matter ratio (GWR). We included 321 consecutive patients admitted to our institution after resuscitation for out-of-hospital cardiopulmonary arrest with circulation resumption over 6 years. A machine learning model using head CT images with transfer learning was used to predict the neurological outcomes at 1 month. These predictions were compared with the predictions of GWR for multiple regions of interest in head CT using receiver operating characteristic (ROC)-area under curve (AUC) and precision recall (PR)-AUC. The regions of focus were visualized using a heatmap. Both methods had similar ROC-AUCs, but the machine learning model had a higher PR-AUC (0.73 vs. 0.58). The machine learning-focused area of interest for classification was the boundary between gray and white matter, which overlapped with the area of focus when diagnosing hypoxic- ischemic brain injury. The machine learning model for predicting poor outcomes had superior accuracy to conventional methods and could help optimize treatment.

Machine learning-based analysis of regional differences in out-of-hospital cardiopulmonary arrest outcomes and resuscitation interventions in Japan.

Refining out-of-hospital cardiopulmonary arrest (OHCA) resuscitation protocols for local emergency practices is vital. The lack of comprehensive evaluation methods for individualized protocols impedes targeted improvements. Thus, we employed machine learning to assess emergency medical service (EMS) records for examining regional disparities in time reduction strategies. In this retrospective study, we examined Japanese EMS records and neurological outcomes from 2015 to 2020 using nationwide data. We included patients aged ≥ 18 years with cardiogenic OHCA and visualized EMS activity time variations across prefectures. A five-layer neural network generated a neurological outcome predictive model that was trained on 80% of the data and tested on the remaining 20%. We evaluated interventions associated with changes in prognosis by simulating these changes after adjusting for time factors, including EMS contact to hospital arrival and initial defibrillation or drug administration. The study encompassed 460,540 patients, with the model's area under the curve and accuracy being 0.96 and 0.95, respectively. Reducing transport time and defibrillation improved outcomes universally, while combining transport time and drug administration showed varied efficacy. In conclusion, the association of emergency activity time with neurological outcomes varied across Japanese prefectures, suggesting the need to set targets for reducing activity time in localized emergency protocols.

Association of multiple rib fractures with the frequency of pneumonia in the post-resuscitation period.

Purpose: Successful cardiopulmonary resuscitation is associated with a high incidence of chest wall injuries. However, few studies have examined chest wall injury as a risk factor for respiratory complications after cardiopulmonary resuscitation. Therefore, herein, we investigated the association of multiple rib fractures on the incidence of post-resuscitation pneumonia. Methods: This single-centre retrospective cohort study enrolled adult, nontraumatic, out-of-hospital cardiac arrest patients who maintained circulation for more than 48 h between June 2015 and May 2019. Rib fractures were evaluated by computed tomography on the day of hospital admission. The association with newly developed pneumonia within 7 days of hospitalisation was analysed using a Fine-Gray proportional hazards regression model adjusted for the propensity score of multiple rib fractures estimated from age, sex, presence of witnessed status, bystander CPR, initial rhythm, and total CPR time and for previously reported risk factors for pneumonia (therapeutic hypothermia and prophylactic antibiotics). Results: Overall, 683 patients with out-of-hospital cardiac arrest were treated; 87 eligible cases were enrolled for analysis. Thirty-two (36.8%) patients had multiple rib fractures identified on computed tomography, and 35 (40.2%) patients developed pneumonia. The presence of multiple rib fractures was significantly associated with a higher incidence of pneumonia, consistently both with and without adjustment for background factors (unadjusted hazard ratio 4.63, 95% confidence interval: 2.35-9.13, p < 0.001; adjusted hazard ratio 4.03, 95% confidence interval: 2.08-7.82, p < 0.001). Conclusions: Multiple rib fractures are independently associated with the development of pneumonia after successful resuscitation.

Response to pre-dilatation with POBA can predict target lesion revascularization after DCB angioplasty for de novo small coronary artery lesions.

OBJECTIVE: To assess the determinants of target lesion revascularization (TLR) after drug-coated balloon (DCB) angioplasty for de novo small coronary artery lesions. METHODS: This retrospective study enrolled consecutive lesions from patients that were in a stable condition and had undergone successful DCB treatment for de novo small coronary artery lesions. The study endpoint was TLR and major adverse cardiac events at 12 months. RESULTS: A total of 68 patients with 83 lesions were enrolled in the study. Of these, 11 (13.3%) lesions required TLR. Mean ± SD pre-dilatation balloon diameters were similar in the non-TLR (2.33 ± 0.72 mm) and TLR (2.18 ± 0.36 mm) groups. A comparison of the two groups showed that post/pre-lumen area ratio during pre-dilatation (%) by plain old balloon angioplasty (POBA) was significantly and negatively associated with TLR and the optimal cut-off point was 170%. Cox proportional hazard and multivariate regression analyses showed that post/pre-lumen area ratio was the only independent predictor of TLR (hazard ratio 0.9318; 95% confidence interval 0.9001, 0.9645). CONCLUSION: Greater pre-dilatation using POBA, assessed as the post/pre-lumen area ratio, may be independently associated with a lower 12-month TLR rate in patients undergoing DCB angioplasty for de novo small coronary lesions.

Visual assessment of interactions among resuscitation activity factors in out-of-hospital cardiopulmonary arrest using a machine learning model.

AIM: The evaluation of the effects of resuscitation activity factors on the outcome of out-of-hospital cardiopulmonary arrest (OHCA) requires consideration of the interactions among these factors. To improve OHCA success rates, this study assessed the prognostic interactions resulting from simultaneously modifying two prehospital factors using a trained machine learning model. METHODS: We enrolled 8274 OHCA patients resuscitated by emergency medical services (EMS) in Nara prefecture, Japan, with a unified activity protocol between January 2010 and December 2018; patients younger than 18 and those with noncardiogenic cardiopulmonary arrest were excluded. Next, a three-layer neural network model was constructed to predict the cerebral performance category score of 1 or 2 at one month based on 24 features of prehospital EMS activity. Using this model, we evaluated the prognostic impact of continuously and simultaneously varying the transport time and the defibrillation or drug-administration time in the test data based on heatmaps. RESULTS: The average class sensitivity of the prognostic model was more than 0.86, with a full area under the receiver operating characteristics curve of 0.94 (95% confidence interval of 0.92-0.96). By adjusting the two time factors simultaneously, a nonlinear interaction was obtained between the two adjustments, instead of a linear prediction of the outcome. CONCLUSION: Modifications to the parameters using a machine-learning-based prognostic model indicated an interaction among the prognostic factors. These findings could be used to evaluate which factors should be prioritized to reduce time in the trained region of machine learning in order to improve EMS activities.

The circulating furin-cleaved/mature PCSK9 ratio has a potential prognostic significance in statin-naïve patients with acute ST elevation myocardial infarction.

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, but their biological functions are uncertain. We investigated whether their levels associate with prognosis in patients with acute ST elevation myocardial infarction (STEMI). Methods: We enrolled 160 statin-naïve patients with acute STEMI and followed for 3 years. PCSK9 subtype levels were determined by an enzyme-linked immunosorbent assay before and at five timepoints up to 48 h after emergent coronary intervention. The occurrence of coronary and cardiac events was compared between subjects stratified by the PCSK9 level. Results: One hundred and twenty-six patients completed 3 years of follow-up. In the acute phase, both PCSK9 subtype levels decreased, and thereafter increased from 6 to 48 h (mature: from 198 ± 67 to 334 ± 116 ng/mL, furin-cleaved: from 20 ± 7 to 39 ± 16 ng/mL, both p < 0.01). Major cardiac events occurred in 46 patients. The furin-cleaved/mature PCSK9 ratio at 48 h after coronary intervention predicted the likelihood of experiencing of events; patients in the third tertile had lower event-free survival than those in the first and second tetiles in Kaplan-Meier analysis (p = 0.004). Multivariate Cox regression analysis revealed that this ratio had a greater impact (HR: 1.92; 95% CI: 1.06-3.45, p = 0.03) on events than other known atherosclerosis risk factors. Conclusions: The furin-cleaved/mature PCSK9 ratio was associated with 3-year cardiovascular events in statin-naïve patients with acute STEMI, suggesting a potential link between furin cleavage process of PCSK9 and its effect on prognosis. (249 words).