Causes of prehospital misinterpretations of ST elevation myocardial infarction

Objectives: To determine the causes of software misinterpretation of ST elevation myocardial infarction (STEMI) compared to clinically identified STEMI to identify opportunities to improve prehospital STEMI identification. Methods: We compared ECGs acquired from July 2011 through June 2012 using the LIFEPAK 15 on adult patients transported by the Los Angeles Fire Department. Cases included patients ≥18 years who received a prehospital ECG. Software interpretation of the ECG (STEMI or not) was compared with data in the regional EMS registry to classify the interpretation as true positive (TP), true negative (TN), false positive (FP), or false negative (FN). For cases where classification was not possible using registry data, 3 blinded cardiologists interpreted the ECG. Each discordance was subsequently reviewed to determine the likely cause of misclassification. The cardiologists independently reviewed a sample of these discordant ECGs and the causes of misclassification were updated in an iterative fashion. Results: Of 44,611 cases, 50% were male (median age 65; inter-quartile range 52–80). Cases were classified as 482 (1.1%) TP, 711 (1.6%) FP, 43371 (97.2%) TN, and 47 (0.11%) FN. Of the 711 classified as FP, 126 (18%) were considered appropriate for, though did not undergo, emergent coronary angiography, because the ECG showed definite (52 cases) or borderline (65 cases) ischemic ST elevation, a STEMI equivalent (5 cases) or ST-elevation due to vasospasm (4 cases). The sensitivity was 92.8% [95% CI 90.6, 94.7%] and the specificity 98.7% [95% CI 98.6, 98.8%]. The leading causes of FP were ECG artifact (20%), early repolarization (16%), probable pericarditis/myocarditis (13%), indeterminate (12%), left ventricular hypertrophy (8%), and right bundle branch block (5%). There were 18 additional reasons for FP interpretation (<4% each). The leading causes of FN were borderline ST-segment elevations less than the algorithm threshold (40%) and tall T waves reducing the ST/T ratio below threshold (15%). There were 11 additional reasons for FN interpretation occurring ≤3 times each. Conclusion: The leading causes of FP automated interpretation of STEMI were ECG artifact and non-ischemic causes of ST-segment elevation. FN were rare and were related to ST-segment elevation or ST/T ratio that did not meet the software algorithm threshold

Effect of Interleukin-1 Blockade With Anakinra on Leukocyte Count in Patients With ST-Segment Elevation Acute Myocardial Infarction

Leukocytosis is a common finding in patients with ST elevation myocardial infarction (STEMI) and portends a poor prognosis. Interleukin 1-β regulates leukopoiesis and pre-clinical studies suggest that anakinra (recombinant human interleukin-1 [IL-1] receptor antagonist) suppresses leukocytosis in myocardial infarction. However, the effect of IL-1 blockade with anakinra on leukocyte count in patients with STEMI is unknown. We reviewed the white blood cell (WBC) and differential count of 99 patients enrolled in a clinical trial of anakinra (n = 64) versus placebo (n = 35) for 14 days after STEMI. A complete blood cell count with differential count were obtained at admission, and after 72 h, 14 days and 3 months. After 72 h from treatment, anakinra compared to placebo led to a statistically significant greater percent reduction in total WBC count (− 35% [− 48 to − 24] vs. − 21% [− 34 to − 10], P = 0.008), absolute neutrophil count (− 48% [− 60 to − 22] vs. − 27% [− 46 to − 5], P = 0.004) and to an increase in absolute eosinophil count (+ 50% [0 to + 100] vs. 0% [− 50 to + 62], P = 0.022). These changes persisted while on treatment at 14 days and were no longer apparent at 3 months after treatment discontinuation. We found that in patients with STEMI IL-1 blockade with anakinra accelerates resolution of leukocytosis and neutrophilia. This modulation may represent one of the mechanisms by which IL-1 blockade improves clinical outcomes

Resistance training in humans and mechanical overload in rodents do not elevate muscle protein lactylation

Although several reports have hypothesized that exercise may increase skeletal muscle protein lactylation, empirical evidence in humans is lacking. Thus, we adopted a multifaceted approach to examine if acute and subchronic resistance training (RT) altered skeletal muscle protein lactylation levels. In mice, we also sought to examine if surgical ablation-induced plantaris hypertrophy coincided with increases in muscle protein lactylation. To examine acute responses, participants’ blood lactate concentrations were assessed before, during, and after eight sets of an exhaustive lower body RT bout (n = 10 trained college-aged men). Vastus lateralis biopsies were also taken before, 3-h post, and 6-h post-exercise to assess muscle protein lactylation. To identify training responses, another cohort of trained college-aged men (n = 14) partook in 6 weeks of lower-body RT (3x/week) and biopsies were obtained before and following the intervention. Five-month-old C57BL/6 mice were subjected to 10 days of plantaris overload (OV, n = 8) or served as age-matched sham surgery controls (Sham, n = 8). Although acute resistance training significantly increased blood lactate responses ~7.2- fold (p \u3c 0.001), cytoplasmic and nuclear protein lactylation levels were not significantly altered at the post-exercise time points, and no putative lactylation-dependent mRNA was altered following exercise. Six weeks of RT did not alter cytoplasmic protein lactylation (p = 0.800) despite significantly increasing VL muscle size (+3.5%, p=0.037), and again, no putative lactylation-dependent mRNA was significantly affected by training. Plantaris muscles were larger in OV versus Sham mice (+43.7%, p \u3c 0.001). However, cytoplasmic protein lactylation was similar between groups (p = 0.369), and nuclear protein lactylation was significantly lower in OV versus Sham mice (p \u3c 0.001). The current null findings, along with other recent null findings in the literature, challenge the thesis that lactate has an appreciable role in promoting skeletal muscle hypertrophy

Short-term prognostic implications of serum and urine neutrophil gelatinase-associated lipocalin in acute heart failure:findings from the AKINESIS study

AIMS: Kidney impairment has been associated with worse outcomes in acute heart failure (AHF), although recent studies challenge this association. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker of kidney tubular injury. Its prognostic role in AHF has not been evaluated in large cohorts. The present study aimed to determine if serum NGAL (sNGAL) or urine NGAL (uNGAL) is superior to creatinine for predicting short-term outcomes in AHF. METHODS AND RESULTS: The study was conducted in an international, multicentre, prospective cohort consisting of 927 patients with AHF. Admission and peak values of sNGAL, uNGAL and uNGAL/urine creatinine (uCr) ratio were compared to admission and peak serum creatinine (sCr). The composite endpoints were death, initiation of renal replacement therapy, heart failure (HF) readmission and any emergent HF-related outpatient visit within 30 and 60 days, respectively. The mean age of the cohort was 69 years and 62% were male. The median length of stay was 6 days. The composite endpoint occurred in 106 patients and 154 patients within 30 and 60 days, respectively. Serum NGAL was more predictive than uNGAL and the uNGAL/uCr ratio but was not superior to sCr (area under the curve [AUC]; admission sNGAL 0.61 [95% confidence interval (CI) 0.55-0.67] and 0.59 [95% CI 0.54-0.65], peak sNGAL 0.60 [95% CI 0.54-0.66] and 0.57 [95% CI 0.52-0.63], admission sCr 0.60 [95% CI 0.54-0.64] and 0.59 [95% CI 0.53-0.64] [area under the curve: admission sNGAL 0.61, 95% confidence interval (CI) 0.55-0.67, and 0.59, 95% CI 0.54-0.65; peak sNGAL: 0.60, 95% CI 0.54-0.66, and 0.57, 95% CI 0.52-0.63; admission sCr: 0.60, 95% CI 0.54-0.64, and 0.59, 95% CI 0.53-0.64, at 30 and 60 days, respectively], peak sCr 0.61 [95% CI 0.55-0.67] and 0.59 [95% CI 0.54-0.64] at 30 and 60 days, respectively). NGAL was not predictive of the composite endpoint in multivariate analysis. CONCLUSIONS: Serum NGAL outperformed uNGAL but neither was superior to admission or peak sCr for predicting adverse events

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure

Background: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure. Methods and Results: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r < 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitali-zation. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization. Conclusions: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury bio-marker may prognosticate WRF for heart failure hospitalization

Decongestion, kidney injury and prognosis in patients with acute heart failure

Background: In patients with acute heart failure (AHF), the development of worsening renal function with appropriate decongestion is thought to be a benign functional change and not associated with poor prognosis. We investigated whether the benefit of decongestion outweighs the risk of concurrent kidney tubular damage and leads to better outcomes.& nbsp;Methods: We retrospectively analyzed data from the AKINESIS study, which enrolled AHF patients requiring intravenous diuretic therapy. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and B-type natriuretic peptide (BNP) were serially measured during the hospitalization. Decongestion was defined as >= 30% BNP decrease at discharge compared to admission. Univariable and multivariable Cox models were assessed for oneyear mortality.& nbsp;Results: Among 736 patients, 53% had >= 30% BNP decrease at discharge. Levels of uNGAL and BNP at each collection time point had positive but weak correlations (r = 30% BNP decrease was a significant predictor after multivariable adjustment.& nbsp;Conclusions: Among AHF patients treated with diuretic therapy, decongestion was generally not associated with kidney tubular damage assessed by uNGAL. Kidney tubular damage with adequate decongestion does not impact outcomes; however, kidney injury without adequate decongestion is associated with a worse prognosis

Interleukin‐1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST‐Segment–Elevation Myocardial Infarction

Background ST‐segment–elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin‐1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C‐reactive protein) levels during the first 14 days in patients with ST‐segment–elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo‐controlled, double‐blind, clinical trial in 99 patients with ST‐segment–elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39–120] versus 214 [interquartile range, 131–394] mg·day/L; P\u3c0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end‐systolic volume (median, 1.4 [interquartile range, −9.8 to 9.8] versus −3.9 [interquartile range, −15.4 to 1.4] mL; P=0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, −1.6% to 10.2%] versus 2.7% [interquartile range, −1.8% to 9.3%]; P=0.61) at 12 months. The incidence of death or new‐onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [P=0.046] and 0% versus 11.4% [P=0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P=0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P=0.016). Conclusions In patients presenting with ST‐segment–elevation myocardial infarction, interleukin‐1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299

Clinical Trials in Head Injury

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63185/1/089771502753754037.pd