Serial Biomarker Research Articles

Reverce: Randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan.

557 Background: The optimal treatment sequence in current standard care for patients (pts) with anti-EGFR antibodies-naïve metastatic colorectal cancer (mCRC) is cetuximab (C) followed by regorafenib (R). The objective of this randomized phase II trial is to evaluate efficacy and safety of the therapeutic sequence of R followed by C compared with that of C followed by R for mCRC pts. Methods: Pts with KRAS exon 2 wild-type mCRC after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with R followed by C ± irinotecan (R-C arm) or reverse sequence (C ± irinotecan followed by R; C-R arm). The primary endpoint was OS. Key secondary endpoints included PFS with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and QOL. The exploratory endpoint was serial biomarker analyses including oncogenic alterations from ctDNA or multiple serum proteins. Results: Between November 2013 and September 2016, 101 pts (51 in the R-C arm and 50 in the C-R arm) were randomized and eligible for efficacy analysis. Baseline characteristics were well-balanced in both arms. Bevacizumab had been previously administered in 96% and 98% pts in R-C and C-R, respectively. Sequential treatment was succeeded in 86% pts in both arms. After a median follow-up of 29.0 months with 81 death events, median OS in R-C and C-R were 17.4 and 11.6 months, respectively (stratified logrank P = 0.0293), with a hazard ratio (HR) of 0.61 for OS (95% CI, 0.39–0.96). HR for PFS1 (R in R-C versus C in C-R) was 0.97 (95% CI, 0.61–1.54), whereas that for PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI, 0.17–0.50). No unexpected safety signals were observed in both arms. OS results in RAS/RAF wild type populations with ctDNA analysis at study entry (n = 86) were similar to those of overall population. Conclusions: This was the first randomized study to compare the two therapeutic sequences of R and C for mCRC, suggesting R followed by C is the preferred sequence. Comparable PFS1 and remarkable PFS2 improvement may lead to a longer OS in R-C sequence. The results of detailed biomarker analysis would be also reported. Clinical trial information: UMIN000011294.

Optimizing Management of Heart Failure by Using Echo and Natriuretic Peptides in the Outpatient Unit.

Chronic heart failure (HF) is an important public health problem and is associated with high morbidity, high mortality, and considerable healthcare costs. More than 90% of hospitalizations due to worsening HF result from elevations of left ventricular (LV) filling pressures and fluid overload, which are often accompanied by the increased synthesis and secretion of natriuretic peptides (NPs). Furthermore, persistently abnormal LV filling pressures and a rise in NP circulating levels are well known indicators of poor prognosis. Frequent office visits with the resulting evaluation and management are most often needed. The growing pressure from hospital readmissions in HF patients is shifting the focus of interest from traditionally symptom-guided care to a more specific patient-centered follow-up care based on clinical findings, BNP and echo. Recent studies supported the value of serial NP measurements and Doppler echocardiographic biomarkers of elevated LV filling pressures as tools to scrutinize patients with impending clinically overt HF. Therefore, combination of echo and pulsed-wave blood-flow and tissue Doppler with NPs appears valuable in guiding ambulatory HF management, since they are potentially useful to distinguish stable patients from those at high risk of decompensation.

Real‐Life Use of Neurohormonal Antagonists and Loop Diuretics in Chronic Heart Failure: Analysis of Serial Biomarker Measurements and Clinical Outcome

We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF.

Sensitive Troponin I and Stress Testing in the Emergency Department for the Early Management of Chest Pain Using 2-Hour Protocol.

Despite improvements in identifying high-risk patients with non-ST segment ACS (acute coronary syndrome), low risk patients presenting with atypical chest pain and non-diagnostic Electrocardiogram (ECG) continued to undergo unnecessary admissions and testing. Since 1992, our chest pain protocol included using 4-hour serial biomarkers from ED admission in combination with stress testing to evaluate these patients. Our study aimed at determining whether a new accelerated diagnostic protocol using sensitive cardiac troponin I (cTnI) 2 hours after admission to the ED followed by stress testing is safe and effective in emergency settings, allowing for appropriate triage, earlier discharge and reducing costs. We conducted a single center randomized trial at Presence St. Francis Hospital Chest pain center in Evanston, Illinois enrolling sixty-four consecutive patients with atypical chest pain and non-diagnostic ECG, participants were randomized to accelerated 2 hrs protocol or our pre-existing 4-hrs protocol. Sixty patients completed the protocol and were randomized to either a 2-hour (29 patients) or 4-hour protocol using both I-STAT and PATHFAST cTnI (31 Patients). Troponin I was evaluated at 0 and at 2 hours from ED presentation with and additional draw for patients in the 4-hour rule out-group. Patients with normal serial biomarkers were then evaluated with stress testing and qualified for earlier discharge if the stress test was negative, while those with a positive biomarker at any time were admitted. Thirty-six patients had exercise treadmill stress test and 24 patients had either nuclear or Echo stress test. Fifty-three patients had a normal stress test and were discharged home. One patient in the 4-hour group with normal serial troponins developed ventricular tachycardia/fibrillation during the recovery period of a regular stress test. Six patients had a positive PATHFAST cTnI and a normal I-STAT cTnI at 2-hours. Two out of these six patients evaluated by coronary angiography. One patient had severe tortuous coronaries but no significant obstructive lesion and one had a severe CAD who needed Coronary artery bypass grafting (CABG). Three of the six patients had a normal stress test and one patient decided to leave without further testing. None of the patients with a normal stress test had a major cardiac event or adverse cardiac outcome at six-month follow up. This study demonstrates that the 2 hours accelerated protocol using high sensitivity Troponin assay at 0 and 2 hours with comprehensive clinical evaluation and ECG followed by stress testing might be successful in identifying low-risk patient population who may benefit from early discharge from ED reducing associated costs and length of stay.

Plasma Levels of MicroRNA-155 Are Upregulated with Long-Term Left Ventricular Assist Device Support.

Left ventricular assist device (LVAD) therapy unloads the failing heart but exposes the human body to unique pathophysiologic demands such as continuous blood flow and complete univentricular support, which are associated with increased risk of adverse clinical outcomes. MicroRNAs (miRNAs) are 22–23 nucleotide RNAs involved in regulation of multiple biologic processes including the pathogenesis of heart failure (HF). Thus, measurement of miRNAs may have potential in both diagnostics as circulating biomarkers and in therapeutics for targeted interventions. We examined 23 distinct miRNAs that have previously been shown to play a role in HF pathogenesis and measured them in 40 individuals both before continuous-flow LVAD implantation and at a median of 96.5 days after implantation. Quantitative real-time polymerase chain reaction was performed for miRNA amplification, and 19 miRs were included in statistical analysis. Wilcoxon signed-rank tests were used to compare within-patient median relative quantification values pre- and post-LVAD placement. The median age of patients was 67 years, and 57.5% were at Interagency Registry for Mechanically Assisted Circulatory Support level 1–2. After LVAD support, only miR-155 was found to be statistically significant (p < 0.002), with an upregulation in plasma expression levels with LVAD support, which persisted regardless of the direction of change in serial HF biomarker levels. MicroRNA-155, which has been shown to play a central role in inflammation and neovascularization, was upregulated with long-term LVAD support. If validated by future studies, miR-155 may help further inform on underlying LVAD physiology and has a role as a therapeutic target in this patient population.

Biological variation of extracellular matrix biomarkers in patients with stable chronic heart failure

Extracellular matrix (ECM) biomarkers such as matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are pathophysiological key, prognostic marker and therapeutic target in chronic heart failure (HF). Serial measurements of MMPs and TIMPs may be useful for guidance of these applications. However, interpretation of time-dependent changes requires knowledge about the biological variation of ECM biomarkers. We performed measurements of MMP-2, MMP-9, TIMP-1, and TIMP-4 in 50 patients with chronic HF who met rigid criteria for clinical stability at 3-h, 6-h, 1-week and 2-week time intervals. In addition, clinical and haemodynamic assessment was performed at baseline, at 1- and 2-week intervals. Haemodynamic variables were measured using inert gas rebreathing and impedance cardiography. Heart rhythm was monitored with external ECG event recorders throughout the complete study. Reference change values (RCVs) and minimal important differences (MIDs) were determined for MMP-2, MMP-9, TIMP-1, and TIMP-4. Clinical and haemodynamic variables were stable over time. Depending on the time-interval, RCVs ranged between 4.9 and 11.7% for MMP-2, 26.4 and 56.7% for MMP-9, 10.8 and 30.7% for TIMP-1, and 16.0 and 47.4% for TIMP-4, respectively. The MIDs varied between 43.38 and 65.22ng/ml for MMP-2, 28.71 and 40.96ng/ml for MMP-9, 52.32 and 156.07ng/ml for TIMP-1, and 293.92 and 798.04pg/ml for TIMP-4, respectively. The biological variation of ECM biomarkers differs with respect to individual biomarkers and time intervals. MMP-2 may be most suitable for serial biomarker measurements, as the biological variation is low irrespective of the time interval between measurements.

Unique prefrontal GABA and glutamate disturbances in co-occurring bipolar disorder and alcohol dependence

Bipolar disorder (BD) and alcohol dependence (AD) frequently co-occur, and co-occurring BD and AD are associated with devastating public health costs. Minimal neurobiological research exists to guide the development of effective treatments for this treatment-resistant population. We believe the present study represents the first investigation of prefrontal gamma-aminobutyric acid (GABA) and glutamate levels in co-occurring BD and current AD. The participants were 78 individuals who met DSM-IV criteria for BD I/II and current AD (n=20), BD I/II alone (n=19), current AD alone (n=20) or no diagnosis (n=19). The participants completed a baseline diagnostic visit, then returned approximately 4 days later for a two-dimensional J-resolved proton magnetic resonance spectroscopy (1H-MRS) acquisition in dorsal anterior cingulate cortex (dACC). All participants were required to demonstrate ⩾1 week of abstinence from alcohol/drugs via serial biomarker testing before 1H-MRS. A 2 × 2 factorial analysis of variance of cerebrospinal fluid (CSF)-corrected GABA/water concentrations demonstrated a significant BD × AD interaction (F=2.91, P<0.05), signifying uniquely low levels of GABA in BD+AD; this effect doubled when the sample was restricted to individuals who consumed alcohol within 2 weeks of 1H-MRS. There were no overall effects of BD/AD on CSF-corrected glutamate/water levels. However, the BD × AD interaction, signifying uniquely low levels of glutamate in BD+AD, approached statistical significance (F=3.83, P=0.06) in individuals who consumed alcohol within 2 weeks of 1H-MRS. The dACC GABA levels were significantly, negatively associated with Barratt Impulsiveness Scale (r=−0.28, P=0.02) and Obsessive Compulsive Drinking Scale (r=−0.35, P<0.01) scores. If replicated, these results may suggest that future treatment studies should preferentially evaluate therapeutics in BD+AD known to increase prefrontal GABA and glutamate levels.

Biomarkers of Endocrine, Muscle, and Inflammatory Health Track Training Load of a Collegiate Soccer Season

Blood biomarkers signal health and performance concerns in athletes. However, serial comprehensive biomarker measurement to detect overtraining in elite soccer athletes remains unstudied. PURPOSE: To determine if comprehensive biomarker assessment of endocrine, muscle, and inflammatory health change with training progression in collegiate soccer players. METHODS: A comprehensive panel of 14 biomarkers was assessed in blood samples from 20 NCAA Division I male soccer players (mean±SD; height 181±6cm, body mass 77.9±6.2kg, BF% 11.9±2.4%, VO2max 52.9±6.1 mL[BULLET OPERATOR]kg-1[BULLET OPERATOR]min-1) at 5 time points: prior to the start of preseason (PS), and in season at week 1 (W1), W4, W8, and W12. Blood samples from W1-W12 were obtained 32–34 hours post-match. PlayerLoad (PL) was recorded daily with GPS units. Significant changes in biomarkers over time were assessed via repeated measures ANOVA (α < 0.05) and the degree to which biomarkers explained PL were examined using stepwise regression. RESULTS: Total testosterone (T, mean±SD; ng[BULLET OPERATOR]dL-1) was lower at W1 (588±151) vs PS (665±198, p= 0.029) and W8 vs W4 (565±147, 645±170, p= 0.034). Free T (ng[BULLET OPERATOR]dL-1) was also lower at W1 (103±24) and W12 (99±33) vs PS (127±35, p< 0.025). Free T at W1 (103±24) and W12 (99±33) were decreased vs W4 (125±32, p< 0.022). No differences over time occurred for free cortisol (FC) and total cortisol (TC); however, FC (μg[BULLET OPERATOR]dL-1) was elevated at PS, W1, and W4 (1.02±0.41, 1.09±0.17, 0.94±0.35) compared to the reference range (ref.) (0.07-0.93 (μg[BULLET OPERATOR]dL-1) and TC was elevated W1 (22.1 ± 2.1) vs the ref. (4.6-20.6 μg[BULLET OPERATOR]dL-1). Growth hormone (GH), lactate dehydrogenase, SHBG, IGF1, and TSH remained unchanged over time. Creatine kinase (CK) was elevated at W1 (820± 899 U[BULLET OPERATOR]L-1; ref. 44-196 U[BULLET OPERATOR]L-1) and exhibited a main effect for time (p= 0.001) while myoglobin did not change. IL-6 (pg[BULLET OPERATOR]mL-1) was increased W8 vs W1 (1.61±.87, 0.83±0.20, p= 0.007), however IL-1β remained unchanged over time. Changes in PL were explained by T4, A1C, Free T, glucose, GH, and CK (R2=0.39, β=-0.490, p=0.001). CONCLUSION: Comprehensive biomarker testing detected reduced FT, elevated TC, and increased CK after PS, consistent with a net catabolic state after PS, without apparent overtraining. Variation (39%) in PL was explained by routine monitoring indicating that these biomarkers track training progression.

Personalized Treatment of Heart Failure with Biomarker Guidance Using a Novel Disease Severity Score

We propose a novel Myocardial Injury Summary Score (MISS) integrating the 4 biomarkers suggested by the 2013 American College of Cardiology/American Heart Association guidelines for management of heart failure. In this case series, we examined 4 heart failure patients who received treatment guided by the biomarker results and 4 patients who received routine clinical management with no information about the biomarkers. Most of the patients receiving biomarker-guided management had medications adjusted based on the biomarker values, while no changes were recommended for patients in the biomarker-blinded category. This case series suggests that biomarker-guided therapy with serial biomarker values leads to timely therapeutic adjustment and that biomarker values as a composite score can be used effectively to measure the severity of heart failure.

A multimarker multi‐time point‐based risk stratification strategy in acute heart failure: results from the RELAX‐AHF trial

We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF). Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91]. In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy.

P239 A novel user friendly model to identify key predictors of corticosteroid utilization in newly diagnosed patients with ulcerative colitis

Background: Corticosteroid (CS) use in ulcerative colitis (UC) has been identified as a poor prognostic marker. However, key predictors for CS utilization at the time of UC diagnosis are poorly defined. We aimed to develop and internally validated a predictive model to approximate the risk of CS utilization over the course of disease in newly diagnosed UC patients. Methods: Newly diagnosed UC patients from a US nationwide cohort treated in the VA health care system were followed over time to evaluate factors predictive of CS use. Multivariate logistic regression was performed. Model development was performed in a random 2/3 of the total cohort and then validated in the remaining 1/3 of the cohort. The primary outcome was to predict use of CS for the management of UC. Candidate predictors included routinely available data at the time of UC diagnosis, including demographics, laboratory results and index colonoscopy findings. Results: 699 patients met the inclusion criteria and followed for median duration of 8 years. 118 sites from 48 states and Puerto Rico were represented. Of 699 patients, 288 patients (41.2%) required CS use for the management of UC. Key predictors for CS utilization selected for the model were: younger age, non-African American ethnicity, presence of hypoalbuminemia as well as IDA at the time of UC diagnosis, pan-colitis/right sided colitis and increased severity of endoscopy disease at index colonoscopy. The AUC for the model based on extent of disease at UC diagnosis was 0.71 (95% CI: 0.66–0.76). The AUC for the model based on severity of disease at UC diagnosis was 0.71 [95% CI: 0.67–0.76]. Model calibration was consistently good in all models (Hosmer-Lemeshow goodness of fit p>0.05). The models performed similarly in the internal validation cohort. The predicted probability of the outcome event is: Probability = 1/[1 + exp(−(β0 + β1X1 + β2X2 + ... + βkXk))] where βj is the regression coefficient for predictor Xj, and β0 is the model intercept (Table 1). Conclusions: We developed and internally validated a novel prognostic model to predict CS use among newly diagnosed patients with UC. This is the first model to incorporate individual risk factors and develop a cumulative risk for identifying CS use. Once externally validated, this prediction model can be used by clinician to identify high risk patients who may require escalation of therapy and closer follow-up with serial biomarkers to potentially avoid the CS use in future.

Comparison of the Infarct Size between the Loading of Ticagrelor and Clopidogrel in Patients with Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Background and ObjectivesTicagrelor is considered a potent antiplatelet agent compared to clopidogrel. However, there are no studies regarding the effect of ticagrelor loading on infarct size in patients with ST-segment elevation myocardial infarction (STEMI) in a primary percutaneous coronary intervention (PCI) setting.Subjects and MethodsIn this single-center, randomized, open-label study, 188 patients who underwent primary PCI for STEMI were enrolled (92 patients in the clopidogrel group and 96 in the ticagrelor group) and compared the infarct size by technetium-99m (Tc-99m) tetrofosmin single-photon emission computed tomography (SPECT) and serial cardiac biomarker levels between the groups. SPECT was performed at a median of 2 days after PCI.ResultsBaseline clinical and procedural characteristics were similar between the groups. Infarct size on SPECT, was similar between the 2 groups (28.1%±34.5% vs. 32.8%±29.2%; p=0.169). At all time-points after PCI (8, 24, and 48 hours), the peak levels of creatine kinase-myocardial band (CK-MB) and troponin T were lower in the clopidogrel group. The clopidogrel group showed lower cumulative troponin T levels than the ticagrelor group (12.59±10.66 vs. 17.67±19.51 ng/mL; p=0.029).ConclusionTicagrelor loading before primary PCI was not associated with reduced myocardial infarct size during the first 48 hours, compared to clopidogrel loading.

The Deferred Consent Model in a Prospective Observational Study Evaluating Myocardial Injury in the Intensive Care Unit.

Informed consent is a hallmark of ethical clinical research. An inherent challenge in critical care research is obtaining consent when patients lack decision-making capacity. One solution is deferred consent, which is often used for studies that are low risk or involve emergency interventions. Our objective was to describe a deferred consent model in a low-risk critical care study. Prognostic Value of Elevated Troponins in Critical Illness Study was a prospective, pilot observational study of critically ill patients in 3 intensive care units, involving serial electrocardiograms and cardiac biomarkers. Newly admitted patients were enrolled over 1 month. When possible, informed consent was obtained a priori from the patient or substitute decision maker (SDM); otherwise, consent was deferred until the patient regained consent capacity or until their SDM was available. Logistic regression analysis was used to determine the association between patient's sex, Acute Physiology and Chronic Health Evaluation II score, study center, person providing consent (patient vs SDM), method of consent (telephone vs in person), and the provision or not of informed consent. The overall consent rate was 80.1% (213 of 266 persons approached). Of the 53 persons declining consent, 37 (69.8%) agreed to the use of data collected up until that point. Over half of all consent encounters were with patients rather than SDMs. Median interval delay between enrollment and the consent encounter was 1 day. On multivariate analysis, the only variable associated with consent was male sex of the patient (odds ratio for males 2.59, confidence interval: 1.19-5.63). Deferred consent facilitates implementation of time-sensitive research protocols until a consent encounter is possible. As a feasible alternative to exclusive a priori consent, the deferred consent model can be useful in low-risk studies in critically ill patients.

Cohort profile of BIOMArCS: the BIOMarker study to identify the Acute risk of a Coronary Syndrome—a prospective multicentre biomarker study conducted in the Netherlands

PurposeProgression of stable coronary artery disease (CAD) towards acute coronary syndrome (ACS) is a dynamic and heterogeneous process with many intertwined constituents, in which a plaque destabilising sequence could lead...

The pregnancy outcome prediction (POP) study: Investigating the relationship between serial prenatal ultrasonography, biomarkers, placental phenotype and adverse pregnancy outcomes

Placental dysfunction is implicated in many major complications of pregnancy associated with adverse maternal and infant outcome, such as preeclampsia, fetal growth restriction and stillbirth. Yet, despite years of intensive research, screening for these complications is still largely based upon clinical grounds rather than ultrasonic and/or biochemical assessment of placental function. One of the few widely employed methods for assessment of risk, low first trimester levels of PAPP-A (Pregnancy Associated Plasma Protein A), was identified through secondary analysis of data collected to identify new methods of screening for Down's syndrome rather than as a purposeful search for screening tests for abnormal placentation. Development of improved methods for population screening requires better mechanistic understanding of the pathways leading to placentally-related complications of human pregnancy. This is in addition to a need for identification of biomarkers which reflect the underlying pathology, while predicting associated disease with high sensitivity and specificity. In this paper, we outline some of the challenges and opportunities in this area. Furthermore, we illustrate how some of these can be addressed in research studies using the example of the Pregnancy Outcome Prediction (POP) study, a prospective cohort study conducted in Cambridge, UK.

Effort Syncope as the Initial Presentation of Pulmonary Hypertension: An Abstract

SESSION TITLE: Student/Resident Case Report Poster - Pulmonary Vascular Disease I SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: Cases of effort syncope have been reported due to aortic stenosis, hypertrophic cardiomyopathy, and congenital heart diseases. Patients with pulmonary artery hypertension (PAH) typically present with dyspnea, fatigue or chest pain. We present a case of effort syncope as the initial manifestation of PAH. CASE PRESENTATION: A 50 year old male with past medical history of adult onset asthma, history of unprovoked deep vein thrombosis (DVT) on Warfarin, dyslipidemia, and hypertension presented as a transfer from an outside hospital for evaluation by ophthalmology for right orbital fracture after having two syncopal episodes on the morning of hospital admission. After running 15 feet at full sprint, he began to experience sudden onset chest tightness, shortness of breath, confusion, dizziness and subsequent collapse with loss of consciousness for 1 minute. He reports similar experiences in the past where he passed out from exertion over the last 10 years. Basic laboratory findings were within normal limits (WNL). Electrocardiogram showed sinus tachycardia, incomplete right bundle branch block, and T wave inversions in anterior and inferior leads. Serial cardiac biomarkers were WNL. proBNP was 373. There was no disease on chest xray. An echocardiogram with bubble study revealed an ejection fraction of 55-60%, paradoxical septal motion, right ventricle (RV) enlargement, thickened RV wall, impaired RV function, moderate-severe PA pressures. There was no pericardial effusion or intracardiac shunt. CTA thorax revealed dilated pulmonary artery. Given a history of DVT, ventilation - perfusion (VQ) scan was performed to evaluate for chronic thromboembolic disease. The VQ scan revealed two perfusion mismatch defects in the right upper lobe and intermediate probability of pulmonary embolus. Dobutamine stress echocardiography was negative for ischemia. Cardiac catheterization showed normal coronaries, normal left ventricular systolic function with ejection fraction 60% with normal wall motion, elevated left ventricular end diastolic pressure, and severe pulmonary hypertension with mean PA pressure 52 mmHG and no response to Flolan challenge. Pulmonary function tests showed normal spirometry, lung volumes and diffusion capacity. Liver function test, HIV, vasculitis panel, cardiolipin antibodies, Factor V Leiden, prothrombin gene, and homocysteine levels were unremarkable. Management included chronic anticoagulation, supplemental oxygen of 4 L NC, and anti-hypertensives. He was referred to specialized center for thrombo-endarterectomy for chronic thromboembolic pulmonary hypertension. DISCUSSION: It is important to recognize the signs and symptoms of PAH which are often subtle and nonspecific. Earlier recognition of the disease can lead to rapid steps toward management of the underlying cause of pulmonary hypertension. CONCLUSIONS: Reference #1: Lowe, MD & Petch, MC. (2000). Syncope after effort. Postgrad Med J, 76: 164-165. DISCLOSURE: The following authors have nothing to disclose: Ezinnaya Ubagharaji, Aiswerya Sampath, Kegan Jessamy, Alka Lamsal-Ghimire, Matthew Hess No Product/Research Disclosure Information

Aortic dissection.

Aortic dissection is a life-threatening condition caused by a tear in the intimal layer of the aorta or bleeding within the aortic wall, resulting in the separation (dissection) of the layers of the aortic wall. Aortic dissection is most common in those 65-75 years of age, with an incidence of 35 cases per 100,000 people per year in this population. Other risk factors include hypertension, dyslipidaemia and genetic disorders that involve the connective tissue, such as Marfan syndrome. Swift diagnostic confirmation and adequate treatment are crucial in managing affected patients. Contemporary management is multidisciplinary and includes serial non-invasive imaging, biomarker testing and genetic risk profiling for aortopathy. The choice of approach for repairing or replacing the damaged region of the aorta depends on the severity and the location of the dissection and the risks of complication from surgery. Open surgical repair is most commonly used for dissections involving the ascending aorta and the aortic arch, whereas minimally invasive endovascular intervention is appropriate for descending aorta dissections that are complicated by rupture, malperfusion, ongoing pain, hypotension or imaging features of high risk. Recent advances in the understanding of the underlying pathophysiology of aortic dissection have led to more patients being considered at substantial risk of complications and, therefore, in need of endovascular intervention rather than only medical or surgical intervention.

Survival analysis with functional covariates for partial follow-up studies

Predictive or prognostic analysis plays an increasingly important role in the era of personalized medicine to identify subsets of patients whom the treatment may benefit the most. Although various time-dependent covariate models are available, such models require that covariates be followed in the whole follow-up period. This article studies a new class of functional survival models where the covariates are only monitored in a time interval that is shorter than the whole follow-up period. This paper is motivated by the analysis of a longitudinal study on advanced myeloma patients who received stem cell transplants and T cell infusions after the transplants. The absolute lymphocyte cell counts were collected serially during hospitalization. Those patients are still followed up if they are alive after hospitalization, while their absolute lymphocyte cell counts cannot be measured after that. Another complication is that absolute lymphocyte cell counts are sparsely and irregularly measured. The conventional method using Cox model with time-varying covariates is not applicable because of the different lengths of observation periods. Analysis based on each single observation obviously underutilizes available information and, more seriously, may yield misleading results. This so-called partial follow-up study design represents increasingly common predictive modeling problem where we have serial multiple biomarkers up to a certain time point, which is shorter than the total length of follow-up. We therefore propose a solution to the partial follow-up design. The new method combines functional principal components analysis and survival analysis with selection of those functional covariates. It also has the advantage of handling sparse and irregularly measured longitudinal observations of covariates and measurement errors. Our analysis based on functional principal components reveals that it is the patterns of the trajectories of absolute lymphocyte cell counts, instead of the actual counts, that affect patient's disease-free survival time.

Correlation between leukocyte count and infarct size in ST segment elevation myocardial infarction.

IntroductionRegarding the inflammatory mechanisms involved in ischemic heart disease, currently the leukocyte count is the subject of studies related to its association with the prognosis and mortality of ST segment elevation myocardial infarction (STEMI). Our aim is correlate the leukocyte count rise with the size of STEMI, evaluated with the area under the curve (AUC) and the peak of necrosis markers release.Material and methodsThis study is a sub-analysis of the TETHYS trial, a clinical trial that evaluated the effects of methotrexate in STEMI. We evaluated the correlation between quantitative variables with Pearson’s correlation, and the variables that did not follow a normal distribution were subjected to logarithmic transformation to base 10. The value of p < 0.05 indicated statistical significance.ResultsMales accounted for 73% of the participants, who had an average age of 59 years. A total of 58% were hypertensive and 53% smokers. The leukocyte count at hospital admission was significantly correlated with the AUC creatine kinase (CK) (r = 0.256, p = 0.021), troponin AUC (r = 0.247, p = 0.026), peak CK (r = 0.270, p = 0.015) and troponin peak (r = 0.233, p = 0.037). The leukocyte count at 72 h was significantly correlated with CK AUC (r = 0.238, p = 0.032), AUC of MB portion of CK (r = 0.240, p = 0.031) and peak CK (r = 0.224, p = 0.045).ConclusionsWhite blood cell count correlates with STEMI size assessed by serial cardiac biomarker levels.

Role of β-Amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment.

To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI). To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI. Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography. Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions. In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups. Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.