Intraoperative plasma proteomic changes in cardiac surgery: In search of biomarkers of post-operative delirium.

PURPOSE: Delirium presents a significant healthcare burden. It complicates post-operative care in up to 50% of cardiac surgical patients with worse outcomes, longer hospital stays and higher cost of care. Moreover, the nature of delirium following cardiac surgery with cardiopulmonary bypass (CPB) remains unclear, the underlying pathobiology is poorly understood, status quo diagnostic methods are subjective, and diagnostic biomarkers are currently lacking. OBJECTIVE: To identify diagnostic biomarkers of delirium and for insights into possible neuronal pathomechanisms. EXPERIMENTAL DESIGN: Comparative proteomic analyses were performed on plasma samples from a nested matched cohort of patients who underwent cardiac surgery. Validation by targeted proteomics was performed in an independent set of samples. Biomarkers were assessed for biological functions and diagnostic accuracy. RESULTS: Forty-seven percent of subjects demonstrated delirium. Of 3803 proteins identified from patient samples by multiplexed quantitative proteomics, 16 were identified as signatures of exposure to CPB, and 11 biomarkers distinguished delirium cases from non-cases (AuROC = 93%). Notable among these biomarkers are C-reactive protein, serum amyloid A-1 and cathepsin-B. CONCLUSIONS AND CLINICAL RELEVANCE: The interplay of systemic and central inflammatory markers sheds new light on delirium pathogenesis. This work suggests that accurate identification of cases may be achievable using panels of biomarkers.

Echocardiographic Evidence of Cardiac Atrophy in the Critically Ill.

The purpose of this explorative study is to determine if critically ill patients experience cardiac atrophy that can be quantified as a loss of left ventricular mass (LVM) and thus detected by echocardiography. DESIGN: Retrospective single-center cohort study. SETTING: Patients admitted to a tertiary medical center in Boston, MA. PATIENTS: Adult critically ill patients with ICU length of stay greater than or equal to 5 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted a retrospective cohort study of 68 patients, of which 42 were included in the final analysis (mean age 60.9 ± 19.2 yr; 47.6% male). The median length of ICU stay was 11.3 days (interquartile range, 6.8-20.1 d). A decrease in mean LVM over the course of admission for critical illness was observed (median 189.11 g [162.82-240.20 g] vs 176.69 g [142.37-226.26 g]; p = 0.01). After adjusting for sex, age, fluid balance, ICU type, dietary orders, time between echocardiograms, and vasopressor use, this decrease in LVM remained consistent (mean difference, -21.30 g; 95% CI, -41.85 to -0.74; p = 0.04). Relative wall thickness (RWT) did not change during admission. CONCLUSIONS: These data reveal that a loss of LVM is present in patients over their ICU stay without a corresponding change in RWT, consistent with cardiac atrophy. Future prospective studies are needed to confirm these findings and identify possible sequelae of this finding.

Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia.

Background Preeclampsia is a prominent risk factor for long-term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A. During pregnancy, elevated activin A levels are associated with impaired cardiac global longitudinal strain at 1 year, but whether these changes persist beyond 1 year is not known. We hypothesized that activin A levels would remain increased more than 1 year after a preeclamptic pregnancy and correlate with impaired cardiac function. Methods and Results To test our hypothesis, we performed echocardiograms and measured activin A levels in women approximately 10 years after an uncomplicated pregnancy (n=25) or a pregnancy complicated by preeclampsia (n=21). Compared with women with a previously normal pregnancy, women with preeclampsia had worse global longitudinal strain (-18.3% versus -21.3%, P=0.001), left ventricular posterior wall thickness (0.91 mm versus 0.80 mm, P=0.003), and interventricular septal thickness (0.96 mm versus 0.81 mm, P=0.0002). Women with preeclampsia also had higher levels of activin A (0.52 versus 0.37 ng/mL, P=0.02) and activin/follistatin-like 3 ratio (0.03 versus 0.02, P=0.04). In a multivariable model, the relationship between activin A levels and worsening global longitudinal strain persisted after adjusting for age at enrollment, mean arterial pressure, race, and body mass index (P=0.003). Conclusions Our findings suggest that both activin A levels and global longitudinal strain are elevated 10 years after a pregnancy complicated by preeclampsia. Future studies are needed to better understand the relationship between preeclampsia, activin A, and long-term cardiac function.

Evaluation of angiogenic factors in the decision to admit women with suspected preeclampsia.

OBJECTIVE: To compare outcomes, specifically development of preeclampsia with severe features (sPE), between angiogenic biomarker-based admission and admission based on routine clinical care. STUDY DESIGN: This secondary analysis of a prospective study evaluated soluble fms-like tyrosine kinase-1 (sFlt1)/placental growth factor (PlGF) ratio in women presenting to triage for preeclampsia evaluation. Biomarkers levels were measured in samples collected from triage and analyzed retrospectively after outcomes were achieved. For this analysis patients would be hypothetically assigned to 'discharged' with a sFlt1/PlGF ratio ≤ 38 and 'admitted' with a sFlt1/PlGF ratio > 85. Development of sPE and other outcomes were then compared using the biomarker and clinical criteria for admission. RESULTS: 459 patients were included in this analysis. Using biomarker criteria, a larger proportion of patients were hypothetically discharged (67.8% vs 51.0%, p < 0.0001). A larger proportion of patients 'admitted' with a high biomarker level developed sPE (69.5% vs 40.9%, p < 0.0001). A sFlt1/PlGF ratio ≤ 38 had a negative predictive value of 96.8% for development of sPE within two weeks. CONCLUSION: Assessment of angiogenic biomarkes that 'discharges' patients with a low sFlt1/PlGF ratio and 'admits' patients with high ratio could result in reduced admissions and increased admission of patients at risk for developing sPE. Randomized trials are needed to determine the effectiveness of angiogenic biomarker use in decision making in a triage setting among women with suspected preeclampsia.

Antepartum Aspirin Administration Reduces Activin A and Cardiac Global Longitudinal Strain in Preeclamptic Women.

Background Approximately 60% of women have Stage B heart failure 1 year after a preeclamptic delivery. Emerging evidence suggests that the profibrotic growth factor activin A, which has been shown to induce cardiac fibrosis and hypertrophy, is elevated in preeclampsia and may be inhibited by aspirin therapy. We hypothesized that preeclamptic women receiving aspirin would have lower activin A levels and reduced global longitudinal strain (GLS), a sensitive measure of cardiac dysfunction, than women who do not receive aspirin. To test our hypothesis, we performed a cohort study of women with preeclampsia or superimposed preeclampsia and compared activin A levels and GLS in parturients who did or did not receive aspirin. Methods and Results Ninety-two parturients were enrolled, of whom 25 (27%) received aspirin (81 mg/day) therapy. GLS, plasma activin A, and follistatin, which inactivates activin A, were measured. Women receiving aspirin therapy had lower median (interquartile range) levels of activin A (8.17 [3.70, 10.36] versus 12.77 [8.37, 31.25] ng/mL; P=0.001) and lower activin/follistatin ratio (0.59 [0.31, 0.93] versus 1.01 [0.64, 2.60] P=0.002) than women who did not receive aspirin, which also remained significant after multivariable analysis. Furthermore, GLS was worse in patients who did not receive aspirin (-19.84±2.50 versus -17.77±2.60%; P=0.03) despite no differences in blood pressure between groups. Conclusions Our study suggests that antepartum aspirin therapy reduced serum activin A levels and improved GLS in preeclamptic patients, suggesting that aspirin may mitigate the postpartum cardiac dysfunction seen in women with preeclampsia.

Effect of blood pressure control in early pregnancy and clinical outcomes in African American women with chronic hypertension.

OBJECTIVE: Chronic hypertension (cHTN) affects 3-5% of all pregnancies and is twice as prevalent in African American (AA) women. AA women develop more severe HTN at an earlier onset and have higher rates of adverse pregnancy outcomes. Blood pressure control during pregnancy is controversial. STUDY DESIGN: This retrospective cohort included AA women with cHTN and singleton pregnancies delivering between January 2013 and December 2016. Patients were classified as not receiving antihypertensives in the first 20 weeks (Group A), on antihypertensives in the first 20 weeks but with an average BP <140/90 during pregnancy (Group B) and on antihypertensives in the first 20 weeks but with average BP during pregnancy ≥140/90 (Group C). Adverse outcomes including severe HTN and preterm delivery <35 weeks was compared between groups. RESULTS: Of the 198 patients included, 68 received at least one AHT before 20 weeks including 45 patients with average BP <140/90 and 23 with average BP ≥140/90 during pregnancy. The incidence of superimposed PE and preterm birth was significantly higher among women with elevated BPs on AHT (39.1% vs 8.9% vs 17.7%, p = 0.01; preterm birth 52.2%, 8.9% and 9.2%, p < 0.001 for Groups C, B and A, respectively). A significantly higher proportion of adverse neonatal outcomes were observed in Group C (78.3%) as opposed to those in Group B (53.3%) or Group A (50.0%; p = 0.04). CONCLUSIONS: Among AA women with cHTN, use of antihypertensives prior to 20 weeks and lower antenatal BP was associated with a decreased risk of adverse maternal and neonatal outcomes.

Angiogenic Factor Estimation as a Warning Sign of Preeclampsia-Related Peripartum Morbidity Among Hospitalized Patients.

Preeclampsia-related morbidity and mortality is rising predominantly because of delayed identification of patients at risk for preeclampsia with severe features and associated complications. This study explored the association between angiogenic markers (sFlt1 [soluble fms-like tyrosine kinase-1]) and PlGF [placental growth factor]) and preeclampsia-related peripartum complications. Normotensive women or those with hypertensive disorders of pregnancy were enrolled. Blood samples were collected within 96 hours before delivery, and angiogenic markers were measured on an automated platform. Our study included 681 women, 375 of which had hypertensive disorders. Of these, 127 (33.9%) had severe preeclampsia, and 71.4% were black. Compared with normotensive women, women with severe preeclampsia had higher levels of sFlt1 (9372.5 versus 2857.0 pg/mL; P<0.0001), lower PlGF (51.0 versus 212.0 pg/mL; P<0.0001), and a high sFlt1/PlGF (212.0 versus 14.0; all P<0.0001). A similar trend in sFlt1, PlGF, and sFlt1/PlGF was found in those women with complications secondary to preeclampsia (all P<0.001). The highest tertile of sFlt1/PlGF was strongly associated with severe preeclampsia in a multivariable analysis. Among patients with a hypertensive disorder of pregnancy, 340 (90.7%) developed postpartum hypertension, of which 50.4% had mild, and 40.3% had severe postpartum hypertension. The sFlt1/PlGF ratio was significantly higher for severe and mild postpartum hypertension compared with women with normal postpartum blood pressures (73.5, 46.0, and 13.0, respectively; P values<0.0001). Furthermore, the highest tertile of antepartum sFlt1/PlGF was associated with postpartum hypertension ( P=0.004). This study demonstrates a significant association between an abnormal angiogenic profile before delivery and severe preeclampsia and peripartum complications.

Hypertensive Diseases of Pregnancy Increase Risk of Readmission With Heart Failure: A National Readmissions Database Study.

OBJECTIVE: To study the association between hypertensive diseases of pregnancy and immediate postpartum development of heart failure in a large national database. PATIENTS AND METHODS: Using the 2013 to 2014 National Readmissions Database, which covered admissions from January 1 through September 30 in years 2013 and 2014, we examined 90-day readmission rates in parturients with a diagnosis of hypertensive disease of pregnancy who were discharged after delivery. The primary outcome was the association between the presence of hypertensive disease of pregnancy and readmission with heart failure within 90 days of delivery discharge. Secondary outcomes included readmission mortality, time between delivery discharge and readmission, length of stay, and costs of readmission. RESULTS: Women with hypertensive disease of pregnancy were more likely to be readmitted with heart failure (1809 of 25,908 readmissions (7.0%) vs 2622 of 89,660 readmissions (2.9%); P<.001). This difference persisted after adjustment for potential cofounders (6.3% vs 3.1%; odds ratio, 2.15; 95% CI, 1.92-2.40; P<.001). Women with a diagnosis of heart failure at readmission were readmitted sooner (11 days vs 23 days; P<.001) and had a longer length of stay (4 days vs 3 days; P<.001) and higher costs of readmission ($10,361 vs $6977; P<.001) than did women without a diagnosis of heart failure. CONCLUSION: Parturients with hypertensive disease of pregnancy were more likely to be readmitted with heart failure within 90 days of delivery. Most patients readmitted with heart failure were readmitted within 2 weeks of discharge after delivery. Patients readmitted with heart failure had substantial health care expenditures.