Yin-Yang 1 transcription factor modulates ST2 expression during adverse cardiac remodeling post-myocardial infarction.

BACKGROUND: The cardioprotective effects of metformin remain poorly defined. Interleukin (IL)-33/ST2L signaling is a novel cardioprotective pathway, which is antagonized by the soluble isoform sST2. No data exist about the regulation of ST2 expression. This study aimed to evaluate the pathophysiological implication of Yin-Yang 1 (Yy1) transcription factor in cardiac remodeling and the expression of the soluble ST2 isoform. METHODS AND RESULTS: Myocardial infarction (MI) was induced in Wistar rats randomly receiving metformin or saline solution by permanent ligation of the left anterior coronary artery. In addition, a model of cardiomyocyte "biochemical strain" was used. Metformin administration improved post-MI cardiac remodeling, an effect that was associated with increased IL-33 and reduced sST2 levels in the myocardium. The anti-remodeling effects of metformin were also associated with a decrease in the transcription factor Yy1 intranuclear level and lower levels of phosphorylated HDAC4 within the cytoplasmic space. These effects were also observed in a cardiomyocyte biochemical strain model, where Yy1 silencing or HDAC4 inhibition blocked sST2 production in cardiomyocytes. Metformin blocked the HDAC4 phosphorylation induced by MI, preventing its export from the nucleus to the cytosol. The presence of dephosphorylated HDAC4 in the nucleus acted as a co-repressor of Yy1, repressing sST2 expression. CONCLUSION: The transcription factor Yy1 regulates sST2 expression, and repression of Yy1 by metformin results in lower levels of sST2 that are associated with favorable myocardial remodeling. The manipulation of YY1 or its co-repressor HDAC4 emerge as new targets to modulate ST2/IL33 signaling and prevent adverse cardiac remodeling.

Polygenic loading for major depression is associated with specific medical comorbidity.

Major depressive disorder frequently co-occurs with medical disorders, raising the possibility of shared genetic liability. Recent identification of 15 novel genetic loci associated with depression allows direct investigation of this question. In cohorts of individuals participating in biobanks at two academic medical centers, we calculated polygenic loading for risk loci reported to be associated with depression. We then examined the association between such loading and 50 groups of clinical diagnoses, or topics, drawn from these patients' electronic health records, determined using a novel application of latent Dirichilet allocation. Three topics showed experiment-wide association with the depression liability score; these included diagnostic groups representing greater prevalence of mood and anxiety disorders, greater prevalence of cardiac ischemia, and a decreased prevalence of heart failure. The latter two associations persisted even among individuals with no mood disorder diagnosis. This application of a novel method for grouping related diagnoses in biobanks indicate shared genetic risk for depression and cardiac disease, with a pattern suggesting greater ischemic risk and diminished heart failure risk.

The role of natriuretic peptides as biomarkers for guiding the management of chronic heart failure.

The current standard treatment of chronic heart failure (HF) is based on clinical judgment, with the goal of achieving the maximally tolerated therapeutic program. The complexity of this approach may contribute to the well-established treatment gaps that exist in HF management; consequently, the risks for morbidity and mortality in this population remain extremely high. Alternative means are needed to improve the outcomes of patients with HF. Natriuretic peptides are biological markers for HF disease--its presence, severity, and prognosis--and show unique interactions with therapeutics known to have benefit in HF. Accordingly, interest has recently developed in "biomarker-guided" care for HF. This approach involves applying these assays to identify patients in need of therapy intensification and to provide an objective "monitor" of disease status. This review examines the biology of natriuretic peptides, discusses the rationale for their use in HF, and details the aggregate experience gained thus far in biomarker-guided care.

Highly sensitive troponin T in patients with acute ischemic stroke.

BACKGROUND: Newly developed troponin assays have superior diagnostic and prognostic performance in acute coronary syndrome (ACS), when compared to conventional troponin assays; however, highly sensitive troponin has not been evaluated in patients with acute ischemic stroke. METHODS: Highly sensitive troponin T (hsTnT) was measured daily during the first 4 days in 193 consecutive patients with acute ischemic stroke without overt ACS or atrial fibrillation. The patients were previously tested normal with a fourth-generation TnT assay. The patients were followed for 47 months, with all-cause and cardiovascular mortality end-points. RESULTS: A total of 33.7% of the patients had hsTnT levels >14 ng/l following admission. Patients with increased hsTnT were older, had decreased hemoglobin levels and increased creatinine, NT-proBNP and CRP levels. hsTnT concentrations at admission were significantly higher in decedents than in survivors. After adjustment for stroke severity, C-reactive protein, age, NT-proBNP and prior heart and/or renal failure, hsTnT levels were not a significant predictor of long-term all-cause or cardiovascular mortality. CONCLUSION: Elevated levels of hsTnT are frequently present in patients with acute ischemic stroke previously tested normal with a fourth-generation TnT assay. hsTnT did not provide additional prognostic information in these subjects.

Serial monitoring of soluble interleukin family member ST2 in patients with acutely decompensated heart failure.

OBJECTIVES: To determine whether serial measures of the interleukin receptor family member soluble ST2 (sST2) provide additional prognostic information to baseline measures for long-term risk stratification of acutely decompensated heart failure (ADHF) patients. METHODS: We prospectively enrolled 72 ADHF patients. Blood samples were collected to measure sST2 concentrations at presentation and on day 4 of hospitalization. All patients were clinically followed, and vital status was registered. RESULTS: Between presentation and day 4, sST2 concentrations decreased from 62 ng/ml (interquartile range 38-105) to 44 ng/ml (interquartile range 26-72; p < 0.001). Both sST2 concentrations at presentation [hazard ratio (HR) 1.011, 95% confidence interval (CI) 1.005-1.016; p < 0.001] and on day 4 (HR 1.015, 95% CI 1.005-1.024; p = 0.003) were independent predictors of mortality. Patients with sST2 ≤ 76 ng/ml at presentation and ≤ 46 ng/ml on day 4 had the lowest mortality rates (3%), whereas those with both sST2 values above these cutoff points had the highest mortality (50%). C index and reclassification analyses demonstrated that the use of serial sST2 measures resulted in an improvement in the accuracy of mortality prediction. CONCLUSIONS: Among ADHF patients, sST2 concentrations tend to decrease following initiation of treatment and are prognostic both at presentation and during hospitalization. Serial sampling of sST2 adds prognostic information and may provide a basis for enhanced clinical decision making.

Diagnostic and prognostic performance of a novel high-sensitivity cardiac troponin T assay compared to a contemporary sensitive cardiac troponin I assay in patients with acute coronary syndrome.

OBJECTIVE: The study sought to compare the clinical performance of two more sensitive cardiac troponin (cTn) assays, a novel high-sensitivity (hs) troponin T assay and a contemporary cTnI assay. METHODS: We measured hs-cTnT (Roche TnThs) and cTnI (Siemens Centaur Ultra) on presentation in 1,384 patients with suspected acute coronary syndrome (ACS) who underwent early invasive strategy within 24 h after presentation. Kaplan-Meier, Cox proportional hazards, and receiver-operating characteristic (ROC) analysis was used to compare their prognostic performance for the prediction of all-cause death and death/MI (myocardial infarction) after a median of 271 days. We also compared the diagnostic performance of these assays on presentation for early diagnosis of non-STEMI. RESULTS: Both hs-cTnT and cTnI were independently predictive of long-term death (OR 3.51 vs. 2.19) and the composite of death/MI (OR 9.24 vs. 3.61), across the spectrum of ACS and in patients without ACS. When used as a continuous variable, ROC analysis demonstrated significantly higher areas under the curve (AUC) for hs-cTnT as compared to cTnI for the prediction of death/MI (0.721 vs. 0.672, P = 0.024), a trend to better prediction of all-cause death (0.721 vs. 0.672, P = 0.093) and significantly higher AUC for early diagnosis of non-STEMI (0.965 vs. 0.901, P < 0.001). CONCLUSION: Using the 99th percentile cutoff for hs-cTnT and cTnI, both assays enable prediction of adverse long-term outcomes and earlier diagnosis of non-STEMI. Used as a continuous variable, the hs-cTnT assay showed superior performance compared to the cTnI assay, especially in regard to prognosis.

Soluble CXCL16 and long-term outcome in acute ischemic stroke.

OBJECTIVE: CXCL16 is a chemokine involved in atherosclerosis by promoting inflammation, lipid accumulation and matrix degradation. The level of circulating CXCL16 has been proposed as a predictor of long-term mortality in acute coronary syndromes. We studied plasma CXCL16 in acute ischemic stroke and examined associations with long-term mortality following the acute event. METHODS: CXCL16 samples were obtained from 244 patients with acute ischemic stroke (age: 69±13 years) daily from presentation to day 5 and at half a year after the stroke. Patients with overt ischemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause and cardiovascular (CV) mortality as end-points. RESULTS: At follow-up, 72 patients had died with 43 due to CV causes. Plasma CXCL16 was stably elevated in the first days after the acute event followed by a marked decrease after 6 months. In patients who subsequently suffered an adverse outcome, CXCL16 levels at 4 days after the initial event were elevated and were moderately associated with mortality. The increase in CXCL16 from day 1 to 4 was a predictor for all-cause and, in particular, CV mortality even after adjustment in the multivariate analysis for established risk factors such as age, the presence of heart/renal failure, troponin, C-reactive protein and stroke severity. CONCLUSIONS: An increase in plasma CXCL16 during the first days after the initial event is associated with an adverse outcome in patients with acute ischemic stroke, supporting the potential pathogenic role of CXCL16 in atherosclerosis and vascular remodelling as well as their major clinical consequences.

Cardiac troponin T concentrations above the 99th percentile value as measured by a new high-sensitivity assay predict long-term prognosis in patients with acute coronary syndromes undergoing routine early invasive strategy.

OBJECTIVE: A recently developed immunoassay for high-sensitivity measurement of cardiac troponin T (hsTnT) allows measurement at the 99th percentile for a normal population with an assay imprecision <10%. It is unclear whether such a low cutpoint (14 ng/L) is helpful for long-term risk stratification of patients with an acute coronary syndrome (ACS) undergoing routine early invasive strategy. PATIENTS AND MAIN OUTCOME MEASURES: Consecutive patients with ACS admitted to a chest pain unit were studied. The usefulness of hsTnT for early diagnosis of myocardial infarction (MI) and prediction of all-cause death or death/MI over a median of 271 days following presentation was compared against the fourth generation cTnT at the 99th percentile cutpoint. RESULTS: Of 1,384 patients with ACS enrolled, 47.8% had non-ST-segment elevation MI (NSTEMI), 26.4% unstable angina, 21.8% STEMI and 4% had non-ACS. Adjusted risk for all-cause death [adjusted HR 8.26 (95%CI: 1.13-66.33), p = 0.038] and death/MI [adjusted HR 2.71 (95% CI: 1.15-6.38), p = 0.023] were significantly higher with hsTnT above the 99th percentile. In particular, among patients with a standard fourth generation cTnT result below the 99th percentile cutoff (0.01 ng/mL), hsTnT improved risk assessment. Mortality risk associated with an elevated hsTnT was present across the spectrum of ACS, as well as in conditions with hsTnT elevations not related to ACS. CONCLUSION: hsTnT at the 99th percentile cutoff is useful for the diagnostic evaluation of patients with ACS, and provides strong and independent predictive power for adverse long-term outcomes even after early invasive strategy.

What is the role of biomarker measurement after cardiac surgery?

Measurements of cardiac troponin (cTn) and natriuretic peptides can predict outcomes after cardiac surgery and may thus assist in decision making about diagnostic and therapeutic steps in this setting. Not every cardiac surgical procedure is associated with the same degree of cTn or natriuretic peptide elevation; the factors known to affect concentrations of these markers include the severity of preoperative coronary artery disease as well as presenting syndrome, while forms of cardioprotection and anesthesia may affect postoperative concentrations of biomarkers. Release of cTn appears to represent irreversibly damaged myocardium; however, clinicians are cautioned when measuring cTn in post-cardiac surgery venues not to assume an elevated concentration is equivalent to regional acute myocardial infarction; indeed, more often than not, excessive values of cTnT or cTnI more typically represent diffuse myocardial injury. Natriuretic peptide release may occur through both states of irreversible dysfunction as well as more reversible states, such as postoperative shock. Indeed, both cTn and natriuretic peptides are unequivocally prognostic for delayed recovery, intensive care unit utilization, as well as short- and longer-term mortalities following cardiac surgery.

Osteoprotegerin concentrations and prognosis in acute ischaemic stroke.

AIM: Concentrations of osteoprotegerin (OPG) have been associated with the presence of vascular and cardiovascular diseases, but the knowledge of this marker in the setting of ischaemic stroke is limited. METHODS AND RESULTS: In 244 patients with acute ischaemic stroke (age: 69 +/- 13 years), samples of OPG were obtained serially from presentation to day 5. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause mortality as the sole end-point. Multivariable predictors of OPG values at presentation included haemoglobin (T = -2.82; P = 0.005), creatinine (T = 4.56; P < 0.001), age (T = 9.66; P < 0.001), active smoking (T = 2.25; P = 0.025) and pulse rate (T = 3.23; P = 0.001). At follow-up 72 patients (29%) had died. Patients with OPG < or =2945 pg mL(-1) at baseline had a significantly improved survival rate on univariate analysis (P < 0.0001); other time-points did not add further prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C-reactive protein levels, troponin T levels, heart and renal failure concentrations of OPG independently predicted long-term mortality after stroke (adjusted hazard ratio, 2.3; 95% CI: 1.1 to 4.9; P = 0.024). CONCLUSION: Osteoprotegerin concentrations measured at admission of acute ischaemic stroke are associated with long-term mortality.

Potential of mid-infrared spectroscopy to aid the triage of patients with acute chest pain.

A total of 1,429 serum samples from 389 consecutive patients with acute chest pain were analyzed with the goal to aid the rapid diagnosis of acute myocardial infarction. To the best of our knowledge this is the largest and most comprehensive study on mid-infrared spectroscopy in cardiology. We were able to identify those signatures in the mid-infrared spectra of the samples, which were specific to either acute myocardial infarction or chest pain of other origin (angina pectoris, oesophagitis, etc). These characteristic spectral differences were used to distinguish between the cause of the donor's acute chest pain using robust linear discriminant analysis. A sensitivity of 88.5% and a specificity of 85.1% were achieved in a blind validation. The area under the receiver operating characteristics curve amounts to 0.921, which is comparable to the performance of routine cardiac laboratory markers within the same study population. The biochemical interpretation of the spectral signatures points towards an important role of carbohydrates and potentially glycation. Our studies indicate that the "Diagnostic Pattern Recognition (DPR)" method presented here has the potential to aid the diagnostic procedure as early as within the first 6 hours after the onset of chest pain.

Erythropoietin treatment in patients with chronic heart failure: a meta-analysis.

BACKGROUND: Anaemia is common in patients with chronic heart failure (HF), and erythropoiesis stimulating proteins (ESPs) are frequently used for its treatment. However, recent studies in patients with malignancies and renal failure have raised concerns about the safety of these agents. OBJECTIVE: To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality. DATA SOURCES: A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed. STUDY SELECTION: Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included. RESULTS: Seven randomised controlled trials were identified that enrolled 650 patients, of whom 363 were treated with ESPs and 287 with placebo. ESP treatment had a significantly lower risk of HF hospitalisation (risk ratio (RR) = 0.59; 95% CI 0.41 to 0.86; p = 0.006).There was no significant difference in the mortality risk between the two groups (RR = 0.69; 95% CI 0.39 to 1.23; p = 0.21). No significant differences were observed in the occurrence of hypertension or venous thrombosis. CONCLUSIONS: In chronic HF, treatment with ESPs is not associated with a higher mortality rate or more adverse events, whereas a beneficial effect on HF hospitalisation is seen. These outcomes are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anaemia correction in patients with chronic HF.

Troponin testing after cardiac surgery.

Single biomarker measurements can predict outcome after cardiac surgery. and may assist in decision making about diagnostic and therapeutic steps following surgery. Although comparative data are relatively lacking some data exist to suggest that among markers of myocardial necrosis, results from cardiac troponin (cTn) measurement may be superior for risk prediction after cardiac surgery to those from the MB isoenzyme of CK (CK-MB). Loss of cardiac troponins from necrotic myocardium is not replenished through re-expression of genes that might increase protein synthesis, and release of cTn appears to represent irreversibly damaged myocardium. Not every cardiac surgical procedure is associated with the same degree of cTn elevation and forms of cardioprotection may im-portantly affect concentrations of cTn after coronary artery bypass grafting. Similarly, less cardiac injury may occur depending on the form of anesthesia used during surgery. Great caution must be exercised when utilizing cTnT or cTnI for diagnosis of post-cardiac surgery regional acute myocardial infarction: in this context clinical factors must be applied at the risk of a false diagnosis. On the other hand, concentrations of both cTnT and cTnI have repeatedly and unequivocally been shown to be prognostic for delayed recov-ery, intensive care unit utilization, as well as short- and longer-term mortality following cardiac surgery.

Advances in heart failure: natriuretic peptide testing.

Natriuretic peptide testing in the form of B-type natriuretic peptide (BNP) or NT-proBNP measurement has revolutionized modern heart failure (HF) diagnostics for those patients with acute symptoms, and promises to have similarly profound effects not only for the earlier recognition of those with HF, but also for the therapy of patients across the entire spectrum of HF. Future efforts are necessary to better understand the complex biology of the natriuretic peptides, to further optimize use of the assays for their measurement, and to gain clarity regarding the appropriate venue for their measurement. The ultimate goal is to recognize more readily and treat the syndrome that is HF, in order to reduce the considerable morbidity and mortality among those so afflicted.

A clinical and biochemical score for mortality prediction in patients with acute dyspnoea: derivation, validation and incorporation into a bedside programme.

BACKGROUND: Risk stratification for patients with acute dyspnoea is a challenging task. No quantitative tool for mortality prediction among patients with acute dyspnoea is available. METHODS: 595 dyspnoeic subjects were enrolled in an emergency department. Clinical and biochemical factors independently predictive of death by 1 year were used to develop a mortality risk prediction tool. RESULTS: Seven factors comprised the final tool: age (x0.3), heart rate (x0.2), blood urea nitrogen (x0.3), New York Heart Association class (x5), amino-terminal pro-B-type natriuretic peptide (NT-proBNP) >or=986 pg/ml (18 points), systolic blood pressure <100 mm Hg (11 points) and presence of a murmur (11 points). A continuous rise in mortality was seen from 1.7% in the lowest score quintile (n = 118; score or=85.5; p<0.001 for trend). Receiver operating characteristic curve analysis of the score's accuracy produced an area under the curve (AUC) of 0.82 (95% CI 0.78 to 0.85) with similar AUCs in subjects with acutely destabilised heart failure (AUC = 0.73, 95% CI 0.67 to 0.79) and those without (AUC = 0.83, 95% CI 0.77 to 0.85, p for the comparison = NS). The score was validated in a separate population of dyspnoeic patients (AUC = 0.73, 95% CI 0.64 to 0.82; p<0.001) and was incorporated into a computer program suitable for near-patient calculation. CONCLUSION: A new risk stratification tool for acutely dyspnoeic patients has been derived and validated.

Rapid screening for major depression in post-myocardial infarction patients: an investigation using Beck Depression Inventory II items.

OBJECTIVE: To determine the ability of three questions from the Beck Depression Inventory II (BDI-II) to detect major depressive disorder (MDD) in a cohort of patients hospitalised for acute myocardial infarction (MI). DESIGN: Prospective observational study. SETTING: Coronary care unit and cardiac step-down unit of an urban academic medical centre. PATIENTS: 131 post-MI patients within 72 h of symptom onset. INTERVENTIONS: Patients were administered the BDI-II and participated in a structured diagnostic interview for MDD. Three individual BDI-II items (regarding sadness, loss of interest and loss of pleasure) were examined individually and in two-question combinations to determine their ability to screen for MDD. MAIN OUTCOME MEASURES: Sensitivity, specificity, negative and positive predictive values and proportion of patients with MDD correctly identified. RESULTS: The individual items and two-question combinations had good sensitivity (76-94%), specificity (70-88%) and negative predictive values (97-99%). Item 1 (sadness) performed the best of the individual items (48% with a positive response to the item had MDD; 3% with a negative response had MDD; over 80% of patients with MDD were correctly identified). A combination of questions about sadness and loss of interest performed best among the two-question combinations (37% with positive response had MDD v 1% with a negative response; 94% of patients with MDD were identified). CONCLUSIONS: One to two questions regarding sadness and loss of interest serve as simple and effective screening tools for post-MI depression.

Elevation in serum troponin I predicts the benefit of tirofiban.

BACKGROUND: Elevations in serum troponins among patients with acute coronary syndromes have been shown to identify those patients who are at high risk for poor outcome and who accrue larger relative benefits from aggressive antiplatelet and antithrombotic therapies. We studied a group of patients from the PRISM-PLUS trial to explore whether simply using serum troponin I, a serum marker of cardiac injury, could predict benefit of GP IIb/IIIa receptor antagonism with tirofiban. METHODS AND RESULTS: For this study, the subjects consisted of 55 patients receiving the combination therapy of tirofiban/heparin, and 55 receiving heparin alone. The baseline characteristics were similar between the two treatment groups. Serial blood samples were obtained over the first 24-hour period following randomization to study drug, and were analyzed for troponin I (TnI) levels. Among those patients with elevated serum TnI (>0.5 ng/ml), the 30-day event rate for death or myocardial infarction (MI) was reduced from 20.6% among the heparin only group to 3.6% for those treated with the combination of tirofiban/heparin, an absolute risk reduction of 17% and relative risk reduction of 83% (p=0.06). Among the TnI negative patients, the rates of death/MI at 30 days were 9.5% and 11.1% among the combination and heparin treated groups respectively (p=NS). CONCLUSION: Irrespective of high-risk clinical factors, including ST segment depression, these data support the hypothesis that serum troponins identify those who benefit from aggressive antiplatelet therapy with tirofiban.

A risk score system for predicting adverse outcomes and magnitude of benefit with glycoprotein IIb/IIIa inhibitor therapy in patients with unstable angina pectoris.

Clinical outcomes of patients with unstable angina are variable. We sought to identify predictors of adverse clinical outcomes in patients with unstable angina and to investigate whether these factors would predict the magnitude of benefit achieved with platelet glycoprotein IIb/IIIa inhibition. We analyzed 20 variables in the 1,915 patients enrolled in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Five independent predictors were identified: age >65 years, prior coronary artery bypass grafting, antecedent aspirin use, antecedent beta-blocker use, and ST depressions on the presenting electrocardiogram. A risk score system was created using these predictors in which patients were assigned 1 point for the presence of each risk factor. There was a progressive increase in the rate of the composite end point of death, myocardial infarction, or refractory ischemia at 7 days with an increasing number of risk factors. For patients treated with heparin alone, the composite end point event rate was 6.5% in the group with 0 or 1 predictor, 14.6% in the group with 2 predictors, 22.7% in the group with 3 predictors, and 37.1% in the group with 4 or 5 predictors (p <0.00001). When dividing patients into low- (0 or 1 point), medium- (2 or 3 points), and high-risk (4 or 5 points) groups, the addition of tirofiban to heparin therapy was associated with no significant benefit in the low-risk group, a 5.2% absolute reduction in the medium-risk group (p = 0.05), and a 16% absolute reduction in the high-risk group (p = 0.0055). Thus, we have developed a risk score system using 5 variables that can be used to identify patients at high risk for death and cardiac ischemic events and who experience the greatest benefit from the addition of a glycoprotein IIb/IIIa inhibitor to their treatment regimen.