Opioid prescription and risk of atrial fibrillation in younger veterans.

BACKGROUND: Opioids may play a part in the development of atrial fibrillation (AF). Understanding the relationship between opioid exposure and AF can help providers better assess the risk and benefits of prescribing opioids. OBJECTIVE: To assess the incidence of AF as a function of prescribed opioids and opioid type. DESIGN: We performed unadjusted and adjusted time-updated Cox regressions to assess the association between opioid exposure and incident AF. PARTICIPANTS: The national study sample was comprised of Veterans enrolled in the Veterans Health Administration (VHA) who served in support of post-9/11 operations. MAIN MEASURES: The main predictor of interest was prescription opioid exposure, which was treated as a time-dependent variable. The first was any opioid exposure (yes/no). Secondary was opioid type. The outcome, incident AF, was identified through ICD-9-CM diagnostic codes at any primary care visit after the baseline period. KEY RESULTS: A total of 609,763 veterans (mean age: 34 years and 13.24% female) were included in our study. Median follow-up time was 4.8 years. Within this cohort, 124,395 veterans (20.40%) were prescribed an opioid. A total of 1,455 Veterans (0.24%) were diagnosed with AF. In adjusted time-updated Cox regressions, the risk of incident AF was higher in the veterans prescribed opioids (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.38-1.57). In adjusted time-updated Cox regressions, both immunomodulating and nonimmunomodulating opioid type was associated with increased risk of incident AF (HR: 1.40; 95% CI: 1.25-1.57 and HR: 1.49; 95% CI: 1.39-1.60), compared to no opioid use, respectively. CONCLUSIONS: Our findings suggest opioid prescription may be a modifiable risk factor for the development of AF.

Facility Variation in Troponin Ordering Within the Veterans Health Administration.

BACKGROUND: Current United States guidelines recommend troponin as the preferred biomarker in assessing for acute coronary syndrome, but recommendations are limited about which patients to test. Variations in troponin ordering may influence downstream health care utilization. METHODS: We performed a cross-sectional analysis of 3,308,131 emergency department (ED) visits in all 121 acute care facilities within the Veterans Health Administration from 2015 to 2017. We quantified the degree to which case mix and facility characteristics accounted for variations in facility rates in troponin ordering. We then assessed the association between facility quartiles of risk-adjusted troponin ordering and downstream resource utilization [inpatient admissions, noninvasive testing (stress tests, echocardiograms), and invasive procedures (coronary angiograms, percutaneous coronary interventions, and coronary artery bypass grafting surgeries)]. RESULTS: The proportion of ED visits with troponin orders ranged from 2.2% to 64.5%, with a median of 37.1%. Case mix accounted for 9.5% of the variation in troponin orders; case mix and differences in facility characteristics accounted for 34.6%. Facilities in the highest quartile of troponin ordering, as compared with those in the lowest quartile, had significantly higher rates of inpatient admissions, stress tests, echocardiograms, coronary angiograms, and percutaneous coronary intervention. CONCLUSIONS: Significant variation in troponin utilization exists across Veterans Health Administration facilities and that variation is not well explained by case mix alone. Facilities with higher rates of troponin ordering were associated with more downstream resource utilization.

Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography.

BACKGROUND: Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. METHODS: A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. RESULTS: One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46-2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01-4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36-3.43; P=0.001). CONCLUSIONS: T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.

Worsening Renal Function during Management for Chronic Heart Failure with Reduced Ejection Fraction: Results From the Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study.

OBJECTIVES: To assess prognostic meaning of worsening renal failure (WRF) occurring during management of chronic heart failure (HF) with reduced ejection fraction. BACKGROUND: When WRF develops during titration of HF medical therapy, it commonly leads to less aggressive care. METHODS: A total of 151 patients enrolled in a prospective, randomized study of standard of care (SOC) HF therapy versus SOC plus a goal N-terminal pro-B type natriuretic peptide (NT-proBNP) < 1000 pg/mL were examined. Cardiovascular (CV) event (defined as worsening HF, hospitalization for HF, significant ventricular arrhythmia, acute coronary or cerebral ischemia, or CV death) at 1 year relative to WRF (defined as any reduction in estimated glomerular filtration rate) 90 days postenrollment were tabulated. RESULTS: Those developing WRF by 3 months had an average 14% reduction in estimated glomerular filtration rate. There was no difference in incidence of WRF between study arms (43% in SOC, 57% in NT-proBNP, P = .29). During the first 3 months of therapy titration, incident WRF was associated with numerically fewer CV events at 1 year compared with those without WRF (mean 0.81 vs 1.16 events, P = .21). WRF was associated trend toward fewer CV events in the SOC arm (hazard ratio 0.45, 95% confidence interval 0.16-1.24, P = .12); the NT-proBNP-guided arm had numerically lower CV event rates regardless of WRF. Subjects with NT-proBNP <1000 pg/mL and WRF received higher doses of guideline directed medical therapies, lower doses of loop diuretics, and had significantly lower CV event rates (P < .001). CONCLUSIONS: Modest degrees of WRF are common during aggressive HF with reduced ejection fraction management, but we found no significant association with CV outcomes. HF care guided by NT-proBNP was not associated with more WRF compared with SOC, and led to benefit regardless of final renal function.

Prognostic Value of Insulin-Like Growth Factor-Binding Protein 7 in Patients with Heart Failure and Preserved Ejection Fraction.

BACKGROUND: The prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF). METHODS AND RESULTS: Baseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R2 = 0.13; P < .0001), amino-terminal pro-B-type NP (R2 = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R2 = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R2 = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome. CONCLUSIONS: Higher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT00095238.

Associations Between Psychological Constructs and Cardiac Biomarkers After Acute Coronary Syndrome.

OBJECTIVE: Psychological constructs are associated with cardiovascular health, but the biological mechanisms mediating these relationships are unknown. We examined relationships between psychological constructs and markers of inflammation, endothelial function, and myocardial strain in a cohort of post-acute coronary syndrome (ACS) patients. METHODS: Participants (N = 164) attended study visits 2 weeks and 6 months after ACS. During these visits, they completed self-report measures of depressive symptoms, anxiety, optimism, and gratitude; and blood samples were collected for measurement of biomarkers reflecting inflammation, endothelial function, and myocardial strain. Generalized estimating equations and linear regression analyses were performed to examine concurrent and prospective relationships between psychological constructs and biomarkers. RESULTS: In concurrent analyses, depressive symptoms were associated with elevated markers of inflammation (interleukin-17: ß = .047; 95% confidence interval [CI] = .010-.083]), endothelial dysfunction (endothelin-1: ß = .020; 95% [CI] = .004-.037]), and myocardial strain (N-terminal pro-B-type natriuretic peptide: ß = .045; 95% [CI] = .008-.083]), independent of age, sex, medical variables, and anxiety, whereas anxiety was not associated with these markers in multivariable adjusted models. Optimism and gratitude were associated with lower levels of markers of endothelial dysfunction (endothelin-1: gratitude: ß = -.009; 95% [CI] = -.017 to - .001]; optimism: ß = -.009; 95% [CI] = -.016 to - .001]; soluble intercellular adhesion molecule-1: gratitude: ß = -.007; 95% [CI] = -.014 to - .000]), independent of depressive and anxiety symptoms. Psychological constructs at 2 weeks were not prospectively associated with biomarkers at 6 months. CONCLUSIONS: Depressive symptoms were associated with more inflammation, myocardial strain, and endothelial dysfunction in the 6 months after ACS, whereas positive psychological constructs were linked to better endothelial function. Larger prospective studies may clarify the directionality of these relationships. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01709669.

Galectin-3 and mineralocorticoid receptor antagonist use in patients with chronic heart failure due to left ventricular systolic dysfunction.

BACKGROUND: Galectin-3 is a prognostic heart failure biomarker associated with aldosterone-induced myocardial fibrosis; mineralocorticoid receptor antagonists (MRAs) may reduce such fibrosis. We sought to examine outcomes of patients with heart failure with reduced ejection fraction (HFrEF) as a function of galectin-3 and MRA therapy. METHODS: A total of 151 patients with chronic HFrEF were categorized by baseline galectin-3 and subsequent MRA therapy trends with regard to cardiovascular (CV) events, left ventricular remodeling, safety, and quality of life, over a mean of 10 months. RESULTS: Although galectin-3 >20 ng/mL was associated with doubling in adjusted risk for CV events, regardless of MRA treatment, there was no difference in CV event rates with regard to MRA use patterns, independent of galectin-3 concentrations. Specifically, in patients with elevated galectin-3 treated with intensified MRA therapy, a significant difference was not detected in CV event rates (P = .79) or the cumulative number of such events (P = .76). Adjusted analysis revealed no difference in time to first CV event if MRA was added/intensified in those with elevated galectin-3 (hazard ratio 0.99, 95% CI 0.97-1.02, P = .74); similarly, cumulative MRA dose was not a specific predictor of benefit. In those with elevated galectin-3, MRA therapy did not affect left ventricular remodeling indices or quality of life at follow-up; these patients had the highest rates of treatment-related adverse events with intensified MRA use. Regardless of MRA use, elevated galectin-3 was associated with more significant renal dysfunction. CONCLUSIONS: Among patients with chronic HFrEF and elevated galectin-3 concentrations, we found no specific benefit from addition or intensification of MRA therapy.

Characterization and prediction of adverse events from intensive chronic heart failure management and effect on quality of life: results from the pro-B-type natriuretic peptide outpatient-tailored chronic heart failure therapy (PROTECT) study.

BACKGROUND: Serious adverse events (SAEs) from heart failure (HF) therapy are frequent; however, techniques to identify at-risk patients are inadequate. Furthermore, the relationship between SAEs, quality of life (QOL), and cardiac structure are unknown. METHODS AND RESULTS: 151 symptomatic patients with systolic HF were followed for a mean of 10 months. In this post hoc analysis, treatment-related SAEs included acute renal failure, dizziness, hypo/hyperkalemia, hypotension, and syncope. At 1 year, 21 treatment-related SAEs occurred. No difference in SAEs existed between the N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided arm and the standard of care arm (P = .20). At baseline, patients who suffered SAEs were less likely to be receiving beta-blockers (85.7% vs 97.7%; P = .009) and had worse functional class and lower chloride levels. Patients who experienced SAEs had less improvement in their Minnesota Living With Heart Failure Questionnaire scores and had a trend toward reduced echocardiographic reverse remodeling over the follow-up period. Univariable and multivariable analyses were conducted to develop a risk score for SAE prediction; patients in the highest risk quartile had the shortest time to first cardiovascular event (P = 0.01). CONCLUSIONS: NT-proBNP-guided HF care is safe. Experiencing treatment-related SAEs is associated with worse QOL and potentially reduced reverse remodeling. A risk score to prospectively predict SAEs in aggressive HF management was developed.

The Current and Potential Clinical Relevance of Heart Failure Biomarkers.

Heart failure is a growing epidemic, and our understanding of the intricacies of its pathophysiology continues to evolve. Over the last decade, biomarkers of heart failure have been extensively investigated, particularly for diagnosis and risk stratification. While the natriuretic peptides remain the gold standard heart failure biomarker, they are plagued by their non-specific nature; furthermore, the strategy of natriuretic peptide-guided care remains elusive. Multiple candidate markers indicative of other physiologic aspects of heart failure have been identified and studied, including soluble ST2, galectin-3, and high-sensitivity cardiac troponins. Each of these biomarkers has the potential to provide unique therapeutically relevant information. Ultimately, a multi-marker approach may be applied to improve care of patients with heart failure. Definitive clinical trials and the use of advanced statistical analytic techniques are needed to truly determine the optimal strategy of biomarker-assisted diagnosis, prognostication, and management of patients who suffer from this devastating condition.

Clinical Biochemistry of Serum Troponin.

Accurate measurement and interpretation of serum levels of troponin (Tn) is a central part of the clinical workup of a patient presenting with chest pain suspicious for acute coronary syndrome (ACS). Knowledge of the molecular characteristics of the troponin complex and test characteristics of troponin measurement assays allows for a deeper understanding of causes of false positive and false negative test results in myocardial injury. In this review, we discuss the molecular structure and functions of the constituent proteins of the troponin complex (TnT, TnC, and TnI); review the different isoforms of Tn and where they are from; survey the evolution of clinical Tn assays, ranging from first-generation to high-sensitivity (hs); provide a primer on statistical interpretation of assay results based on different clinical settings; and discuss potential causes of false results. We also summarize the advances in technologies that may lead to the development of future Tn assays, including the development of point of care assays and wearable Tn sensors for real-time continuous measurement.

Clinical Interpretation of Serum Troponin in the Era of High-Sensitivity Testing.

Cardiac troponin (Tn) plays a central role in the evaluation of patients with angina presenting with acute coronary syndrome. The advent of high-sensitivity assays has improved the analytic sensitivity and precision of serum Tn measurement, but this advancement has come at the cost of poorer specificity. The role of clinical judgment is of heightened importance because, more so than ever, the interpretation of serum Tn elevation hinges on the careful integration of findings from electrocardiographic, echocardiographic, physical exam, interview, and other imaging and laboratory data to formulate a weighted differential diagnosis. A thorough understanding of the epidemiology, mechanisms, and prognostic implications of Tn elevations in each cardiac and non-cardiac etiology allows the clinician to better distinguish between presentations of myocardial ischemia and myocardial injury-an important discernment to make, as the treatment of acute coronary syndrome is vastly different from the workup and management of myocardial injury and should be directed at the underlying cause.

Dying to know: prognosis communication in heart failure.

Prognosis communication in heart failure is often narrowly defined as a discussion of life expectancy, but as clinical guidelines and research suggest, these discussions should provide a broader understanding of the disease, including information about disease trajectory, the experiences of living with heart failure, potential burden on patients and families, and mortality. Furthermore, despite clinical guidelines recommending early discussions, evidence suggests that these discussions occur infrequently or late in the disease trajectory. We review the literature concerning patient, caregiver, and clinician perspectives on discussions of this type, including the frequency, timing, desire for, effects of, and barriers to their occurrence. We propose an alternate view of prognosis communication, in which the patient and family/caregiver are educated about the nature of the disease at the time of diagnosis, and a process of engagement is undertaken so that the patient's full participation in their care is marshalled, and the care team engages the patient in the informed decision making that will guide care throughout the disease trajectory. We also identify and discuss evidence gaps concerning (i) patient preferences and readiness for prognosis information along the trajectory; (ii) best practices for communicating prognosis information; and (iii) effects of prognosis communication on patient's quality of life, mental health, engagement in critical self-care, and clinical outcomes. Research is needed to determine best practices for engaging patients in prognosis communication and for evaluating the effects of this communication on patient engagement and clinical outcomes.

IGFBP7 (Insulin-Like Growth Factor-Binding Protein-7) and Neprilysin Inhibition in Patients With Heart Failure.

BACKGROUND: Increased activity of IGFBP7 (insulin-like growth factor-binding protein-7) is associated with cellular senescence, tissue aging, and obesity. IGFBP7 may be related to heart failure with preserved ejection fraction, a disease of elderly obese people. METHODS AND RESULTS: In a subset of patients with heart failure with preserved ejection fraction (N=228) randomized to receive sacubitril/valsartan versus valsartan, IGFBP7 concentrations were measured at baseline, 12 weeks, and 36 weeks. Patient characteristics and echocardiographic measures including left atrial (LA) size and volume, ratio of early mitral inflow velocity/annular diastolic velocity, and ratio of early diastole/peak late diastolic velocity were assessed as a function of IGFBP7 concentration. Effect of sacubitril/valsartan on IGFBP7 concentrations was analyzed. With increasing baseline IGFBP7 quartiles, LA size and LA volume index (LAVi) were higher (both P<0.001); modest association between IGFBP7 and higher early mitral inflow velocity/annular diastolic velocity ( P=0.03) and early diastole/peak late diastolic velocity ratio ( P=0.04) was also seen. IGFBP7 concentrations were higher in those with LAVi ≥34 mL/m2 compared with lower LAVi at all time points (all P<0.01). IGFBP7 independently predicted LAVi at baseline even in the presence of NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentrations; highest LAVi was seen in those with elevation in both biomarkers. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations over 36 weeks compared with valsartan (adjusted treatment effect, -7%; P<0.001). CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, concentrations of the cellular senescence biomarker IGFBP7 were associated with abnormalities in diastolic filling and LA dilation. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations compared with valsartan. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00887588.

Predicting new-onset HF in patients undergoing coronary or peripheral angiography: results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study.

AIMS: Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions. METHODS AND RESULTS: From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow-up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow-up, 177 (18%) developed new-onset HF. Independent predictors of new-onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino-terminal pro-B type natriuretic peptide and ST2). The c-statistic for the model without biomarkers was 0.69; including biomarkers increased the c-statistic to 0.76 (P < 0.001). A score was developed from the model. Patients in the highest score quintile had shortest time to incident HF compared with lower quintiles (log-rank P < 0.001). Following 100 bootstrap iterations, internal validation was confirmed with Harrell's c-statistic of 0.77. Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers at enrollment was associated with substantial attenuation of predictive value of the risk score. CONCLUSIONS: Patients undergoing coronary/peripheral angiographic procedures are a population at high risk for incident HF. We describe an accurate clinical and biomarker strategy for predicting incident HF and possibly intervening in such patients (NCT00842868).

Serial Heart Rates, Guideline-Directed Beta Blocker Use, and Outcomes in Patients With Chronic Heart Failure With Reduced Ejection Fraction.

A single heart rate (HR) measurement may inform future prognosis in chronic heart failure with reduced ejection fraction (HFrEF). The importance of elevated HR across serial assessment is uncertain, particularly with well-applied guideline-directed medical therapy (GDMT) with beta blockers (BBs). In this post hoc analysis of 129 patients with chronic HFrEF in sinus rhythm, who had aggressive medication titration over 10.6 months, HR and BB use were assessed at each visit (average of 6 visits per patient). All-cause mortality was assessed. At baseline, 81 subjects (62.8%) had HR ≥70 beats/min; 40 subjects (31.0%) had high HR despite being on ≥50% of GDMT BB dose. At final visit, 30.4% of the subjects still had high HR despite achieving ≥50% target BB dose. There were no significant baseline differences in demographics or BB doses in patients with HR <70 vs HR ≥70 beats/min. In adjusted model in which HR was treated as time-dependent covariate, an increase in HR of 10 beats/min was associated with an increased hazard of all-cause mortality during follow-up (adjusted hazard ratio per 10 beats/min = 2.46; 95% confidence interval 1.46-4.16, p <0.001). In conclusion, in well-managed patients with HFrEF, high HR was frequent even after aggressive medication titration, and often despite being on at least 50% of GDMT BB dose. An increase in HR was associated with worse clinical outcomes (Clinicaltrials.gov NCT#00351390).

Systematic Evaluation of Endothelin 1 Measurement Relative to Traditional and Modern Biomarkers for Clinical Assessment and Prognosis in Patients With Chronic Systolic Heart Failure: Serial Measurement and Multimarker Testing.

OBJECTIVES: To define the role of single or serial measurement of endothelin 1 (ET-1) for prognostication beyond traditional and modern markers of risk in heart failure (HF). METHODS: In total, 115 patients with chronic systolic HF were followed for 10 months. Clinical assessment and ET-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), highly sensitive troponin I (hsTnI), soluble ST2 (sST2), and galectin 3 were measured at each visit. RESULTS: Elevated ET-1 was associated with worse HF, lower right ventricular function, higher pulmonary pressure, and higher left atrial volume index despite similar left ventricular function. ET-1 correlated with angiotensin-converting enzyme inhibitor use. A model containing traditional risk factors, ET-1, NT-proBNP, hsTnI, and sST2 best predicted cardiovascular events, and ET-1 improved reclassification. In an adjusted time-integrated model, percent time spent with ET-1 of 5.90 pg/mL or less was predictive of fewer cardiovascular events (odds ratio, 0.75; 95% confidence interval, 0.62-0.91). ET-1 reduction over time was associated with a lower rate of cardiovascular events compared with increasing or stable ET-1 (24.4% vs 50.0%). CONCLUSIONS: ET-1 may be a unique predictor of HF prognosis, complementing other biomarkers in a multimarker profile. Serial measurement of ET-1 may provide additional prognostic information.

A Clinical and Biomarker Scoring System to Predict the Presence of Obstructive Coronary Artery Disease.

BACKGROUND: Noninvasive models to predict the presence of coronary artery disease (CAD) may help reduce the societal burden of CAD. OBJECTIVES: From a prospective registry of patients referred for coronary angiography, the goal of this study was to develop a clinical and biomarker score to predict the presence of significant CAD. METHODS: In a training cohort of 649 subjects, predictors of ≥70% stenosis in at least 1 major coronary vessel were identified from >200 candidate variables, including 109 biomarkers. The final model was then validated in a separate cohort (n = 278). RESULTS: The scoring system consisted of clinical variables (male sex and previous percutaneous coronary intervention) and 4 biomarkers (midkine, adiponectin, apolipoprotein C-I, and kidney injury molecule-1). In the training cohort, elevated scores were predictive of ≥70% stenosis in all subjects (odds ratio [OR]: 9.74; p < 0.001), men (OR: 7.88; p <0.001), women (OR: 24.8; p < 0.001), and those with no previous CAD (OR: 8.67; p < 0.001). In the validation cohort, the score had an area under the receiver-operating characteristic curve of 0.87 (p < 0.001) for coronary stenosis ≥70%. Higher scores were associated with greater severity of angiographic stenosis. At optimal cutoff, the score had 77% sensitivity, 84% specificity, and a positive predictive value of 90% for ≥70% stenosis. Partitioning the score into 5 levels allowed for identifying or excluding CAD with >90% predictive value in 42% of subjects. An elevated score predicted incident acute myocardial infarction during 3.6 years of follow up (hazard ratio: 2.39; p < 0.001). CONCLUSIONS: We described a clinical and biomarker score with high accuracy for predicting the presence of anatomically significant CAD. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases; NCT00842868).