Abelardo Martinez-Rumayor

Biology of the Natriuretic Peptides

The biology of the natriuretic peptide (NP) system is complex, yet highly phylogenetically preserved. It regulates salt and water handling, promotes vasodilatation, and exerts favorable effects on the heart in the context of processes such as heart failure. Prior assumptions about the production of B-type NP (BNP) and its amino-terminal precursor fragment (NT-proBNP) have recently been refuted. It is now recognized that rather than a 1:1 secretion of these 2 NPs, a mixture of cleaved and uncleaved NPs is released by the cardiomyocyte. It is also recognized that BNP is rapidly modified into a mixture of various fragments. Commercial assays for the detection of BNP and NT-proBNP measure a mixture of cleaved and uncleaved NPs as well as varying amounts of degraded BNP. BNP and NT-proBNP are cleared differentially: BNP is actively removed from the bloodstream and also has passive clearance mechanisms, including renal clearance; NT-proBNP is cleared more passively by organs with high rates of blood flow, including the kidney.

Prospective, Comprehensive Assessment of Cardiac Troponin T Testing After Coronary Artery Bypass Graft Surgery

Background— The significance and clinical role of cardiac troponin testing after coronary artery bypass grafting remain unclear. Methods and Results— Cardiac troponin T (cTnT) was measured during the first 24 hours after coronary artery bypass graft surgery in 847 consecutive patients. Only 17 patients (2.0%) had new Q waves or left bundle-branch block after surgery; however, cTnT elevation was observed in nearly all subjects, with a median cTnT concentration of 1.08 ng/mL overall. Direct predictors of postoperative cTnT values included preoperative myocardial infarction (P<0.001), preoperative intraaortic balloon pump (P<0.001), intraoperative/postoperative intraaortic balloon pump (P<0.001), number of distal anastomoses (P=0.005), bypass time (P<0.001), and number of intraoperative defibrillations (P=0.009), whereas glomerular filtration rate (P<0.001), off-pump coronary artery bypass grafting (P=0.003), and use of warm cardioplegia (P=0.02) were inversely associated with cTnT values. A linear association was seen between cTnT levels and length of stay and ventilator hours, and in an analysis adjusted for the Society for Thoracic Surgery Risk Model, cTnT remained independently prognostic for death (odds ratio, 3.20; P=0.003), death or heart failure (odds ratio, 2.04; P=0.008), death or need for vasopressors (odds ratio, 2.70; P<0.001), and the composite of all 3 (odds ratio, 2.57; P<0.001). In contrast to consensus-endorsed cTnT cut points for postoperative evaluation, a cTnT <1.60 ng/mL had a negative predictive value of 93% to 99% for excluding various post–coronary artery bypass graft surgery complications. Conclusions— cTnT concentrations after coronary artery bypass graft surgery are nearly universally elevated, are determined by numerous factors, and are independently prognostic for impending postoperative complications when used at appropriate cut points.

Clinical Uncertainty, Diagnostic Accuracy, and Outcomes in Emergency Department Patients Presenting With Dyspnea

BACKGROUND Dyspnea is a common complaint in the emergency department (ED) and may be a diagnostic challenge. We hypothesized that diagnostic uncertainty in this setting is associated with adverse outcomes, and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) testing would improve diagnostic accuracy and reduce diagnostic uncertainty. METHODS A total of 592 dyspneic patients were evaluated from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Managing physicians were asked to provide estimates from 0% to 100%of the likelihood of acutely destabilized heart failure (ADHF). A certainty estimate of either 20% or lower or 80% or higher was classified as clinical certainty, while estimates between 21% and 79% were defined as clinical uncertainty. Associations between clinical uncertainty,hospital length of stay, morbidity, and mortality were examined. The diagnostic value of clinical judgment vs NT-proBNP measurement was compared across categories of clinical certainty. RESULTS Clinical uncertainty was present in 185 patients (31%), 103 (56%) of whom had ADHF. Patients judged with clinical uncertainty had longer hospital length of stay and increased morbidity and mortality,especially those with ADHF. Receiver operating characteristic analysis of clinical judgment yielded an area under the curve (AUC) of 0.88 in the clinical certainty group and 0.76 in the uncertainty group (P<.001); NT-proBNP testing alone in these same groups had AUCs of 0.96 and 0.91, respectively. The combination of clinical judgment with NT-proBNP testing yielded improvements in AUC. CONCLUSIONS Among dyspneic patients in the ED, clinical uncertainty is associated with increased morbidity and mortality, especially in those with ADHF.The addition of NT-proBNP testing to clinical judgment may reduce diagnostic uncertainty in this setting.

Independent and incremental prognostic value of multimarker testing in acute dyspnea: Results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study

BACKGROUND Acute dyspnea is common in the emergency department (ED) and is associated with mortality. Biomarkers may help stratify risk in this setting. METHODS Among 577 dyspneic subjects we identified 5 candidate biomarkers with prognostic value: amino terminal B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), the interleukin family member ST2, hemoglobin and blood urea nitrogen (BUN); these were assessed using both receiver operating characteristic curve and Cox proportional hazards analyses. Results were validated in a population of dyspneic patients from a distinct cohort. RESULTS At 1 y follow up, 93 (16.1%) patients had died. Independent predictive ability was established in an age-adjusted Cox model containing all markers: NT-proBNP (HR=1.89); CRP (HR=1.95); ST2 (HR=7.17); hemoglobin (HR=1.68); BUN (HR=2.06) (all P<.05). Following categorical assessment based on number of abnormal markers, the 1-y risk of death increased in a monotonic fashion with mortality rates of 0%, 2.0%, 7.8%, 22.3%, 29.3%, and 57.6% respectively; similar results were seen in the validation set. CONCLUSION Simultaneous assessment of pathophysiologically diverse markers in acute dyspnea provides powerful, independent and incremental prognostic information.

Association between C-reactive protein and generalized anxiety disorder in stable coronary heart disease patients

AIMS Comprehensive evaluation of major depressive disorder (MDD), anxiety disorder, and MDD in conjunction with anxiety disorder in stable coronary heart disease (CHD) patients, including cardiac biomarkers such as C-reactive protein (CRP), troponin T (TnT), and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS Cross-sectional study of a consecutive series of 120 stable CHD outpatients (n = 30 with MDD, n = 30 with anxiety disorder, n = 30 with MDD and anxiety disorder, n = 30 with no psychiatric disorder). Psychiatric diagnoses were established by using the structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV). Binomial logistic regression analyses using cut-off scores of biomarkers as dependent variables showed associations between CRP and generalized anxiety disorder (GAD) (P = 0.04), and education (P = 0.004), whereas MDD, and MDD and anxiety disorder did not reach the significance level. TnT showed relationships with hyperlipidaemia (P = 0.009), history of obesity or overweight (P = 0.04), and education (P = 0.04). NT-proBNP was associated with type II diabetes (P = 0.005). CONCLUSION After adjusting for relevant demographic, medical, and psychiatric co-variables, CRP was associated with GAD.

Soluble ST2 Plasma Concentrations Predict 1-Year Mortality in Acutely Dyspneic Emergency Department Patients With Pulmonary Disease

We evaluated the association between ST2 concentrations and mortality at 1 year in 231 acutely dyspneic patients with pulmonary diseases seen in the emergency department. Blood concentrations of ST2 were ascertained; using 1-year survival as the reference standard, receiver operating characteristic curves with resultant area under the curve (AUC) were measured. Cox proportional hazards models identified independent predictors of 1-year death. Hazard curves compared rates of death as a function of ST2 concentration. Concentrations of ST2 were significantly higher in patients with pulmonary diseases compared with 153 subjects without cardiopulmonary disease (0.23 vs 0.11 ng/mL; P = .01). Among patients with pulmonary diseases, concentrations of ST2 were higher among decedents compared with survivors (1.14 ng/mL vs 0.19 ng/mL; P < .001). ST2 had an AUC of 0.72 as a predictor of death (P < .0001). An ST2 of 0.20 ng/mL had a hazard ratio for death of 6.1 (95% confidence interval, 1.8-21.0; P = .004). Compared with patients with lower ST2 concentrations, mortality rates for patients with an enrollment ST2 of 0.20 ng/mL or more diverged early and rose progressively in 1 year (P < .001). ST2 concentrations are frequently elevated in acute pulmonary diseases and are markedly prognostic for death by 1 year.

Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients.

OBJECTIVE This study aimed for a comprehensive evaluation of major depressive disorder (MDD) in stable coronary heart disease (CHD) patients, excluding all other potential psychiatric comorbidities, and including associations with cardiac biomarkers such as C-reactive protein (CRP), troponin T (TnT), and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP). METHODS Cross-sectional study of a consecutive series of 72 stable CHD outpatients (n=30 with MDD, n=42 with no psychiatric disorder). Psychiatric diagnoses were established by using the Structured Clinical Interview for DSM-IV (SCID), and psychiatric assessment was performed on Axis I, Axis III, Axis IV, and Axis V. Regression analyses were performed including CRP, TnT, and NT-proBNP as dependent variables, and MDD, demographics, and comorbid medical conditions as independent variables. RESULTS Stepwise multiple regression analyses showed a significant association between MDD and CRP (beta=0.262, P=.02), excluding all other demographic and medical variables from the models, except age (beta=0.266, P=.02). In addition, the results described a significant relationship between type II diabetes mellitus and TnT (beta=0.267, P=.02), and age and NT-proBNP levels (beta=0.374, P=.001). CONCLUSION Major depressive disorder was associated with elevated CRP levels in a consecutive series of stable CHD patients.

Association Between Anxiety and C-Reactive Protein Levels in Stable Coronary Heart Disease Patients

BACKGROUND Anxiety is highly prevalent among patients with stable coronary heart disease (CHD). However, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. OBJECTIVE This study aimed for a comprehensive evaluation of anxiety in stable CHD patients, in addition to cardiac biomarkers such as C-reactive protein (CRP), troponin T, and amino-terminal pro-B-type brain natriuretic peptide. METHOD The study included 43 CHD patients with anxiety disorder and 42 CHD patients without psychiatric disorder given the Structured Clinical Interview for DSM-IV. RESULTS Regression analyses showed an association between anxiety (anxiety disorder, not otherwise specified) and CRP levels, despite model adjustment for various related demographic and clinical variables. Anxiety was associated with CRP levels. CONCLUSION There are significant associations between anxiety and CHD risk, with a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely CRP. It is not clear whether this association is directly causal or relates to other medical processes among patients with heightened anxiety. The findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well.

Relative value of amino-terminal pro-B-type natriuretic peptide testing and radiographic standards for the diagnostic evaluation of heart failure in acutely dyspneic subjects

To define more clearly the relationship between the information provided by the chest radiograph (CXR) and the natriuretic peptide (NT-proBNP) test as part of the evaluation of dyspneic patients presenting to the emergency department with suspected acute heart failure (HF), we evaluated the PRIDE cohort of 599 patients with and without HF, focusing on blinded NT-proBNP and unblinded CXR information. Clinical characteristics and diagnostic performance for each test were compared. We found that NT-proBNP measurement is superior to routine CXR interpretation for diagnosis or exclusion of acute HF and that normal CXR results should not be used to exclude HF in this population.

Inflammatory markers, amino-terminal pro-brain natriuretic peptide, and mortality risk in dyspneic patients.

Dyspnea is a common emergency department (ED) complaint, and it may be associated with significant mortality risk. We studied 599 dyspneic subjects enrolled in an ED. At 1 year, the role of inflammatory markers (including C-reactive protein [CRP]) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) as independent predictors of mortality was assessed. By 1 year, 91 subjects (15.2%) had died. Among patients who died, the median CRP concentration at admission was significantly higher than in survivors: 47.2 mg/L (449.5 nmol/L; interquartile range [IQR], 10.2-101.9 mg/L [97.1-970.5 nmol/L]) vs 7.25 mg/L (69.5 nmol/L; IQR, 2.2-29.6 mg/L [21.0-281.9 nmol/L]; P < .001). For 1-year mortality, CRP had an area under the receiver operating characteristic curve of 0.76 (95% confidence interval [CI], 0.69-0.80; P < .001). In multivariable analysis, a CRP concentration greater than 14 mg/L was a strong predictor of mortality at 1 year (hazard ratio, 2.47; 95% CI, 1.51-4.02; P < .001). In multivariable models, CRP and NT-proBNP demonstrated independent and additive prognostic value. Among dyspneic patients, CRP levels are significantly associated with mortality at 1 year and show additive value to natriuretic peptide testing for prognosis.