Dominic Kelly

Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction

AIMSnOur aim was to assess the long-term prognostic value of growth differentiation factor-15 (GDF-15) in patients post-acute myocardial infarction (AMI). Growth differentiation factor-15 is a member of the transforming growth factor beta family. Growth differentiation factor-15 is expressed in the myocardium and upregulated due to stress and has been shown to have antiapoptotic actions. Its role in the cardiovascular system however is not well defined. We were interested to see if GDF-15 could provide long-term prognostic value in post-AMI patients. We compared GDF-15 with N-terminal pro-B-type natriuretic peptide (NT-proBNP).nnnMETHODS AND RESULTSnWe recruited 1142 consecutive post-AMI patients [820 men, median (range) age 67 (24-97) years] in a prospective study with a follow-up period of 505 (range 1-2837) days. Growth differentiation factor-15 levels increased with increasing Killip class (P < 0.001) and were correlated with NT-proBNP (r = 0.47, P < 0.001). Using a multivariable Cox proportional hazards model, log GDF-15 (HR 1.77), log NT-proBNP (HR 2.06), age (HR 1.03) Killip class above 1, (HR 1.62), use of beta-blockers (HR 0.54) and past history of MI (HR 1.44) were significant independent predictors of death or heart failure (HF). Predictors of death were log NT-proBNP, log GDF-15, age, eGFR, past history of MI, use of beta-blockers, and use of ACE inhibitors or angiotensin receptor blockers. The C-statistic for GDF-15 for predicting death or HF at 1 year was 0.73 (95% CI: 0.70-0.76, P < 0.001) and was 0.76 (95% CI: 0.70-0.80, P < 0.001) for NT-proBNP. Combining these markers yielded an AUC of 0.81 (95% CI: 0.77-0.85), which exceeded that of GDF-15 (P < 0.001) and NT-proBNP (P = 0.004) alone. The Kaplan-Meier analysis revealed that those patients with above median GDF-15 and NT-proBNP had the highest event rate for death and HF (log rank 50.22, P < 0.001).nnnCONCLUSIONnGrowth differentiation factor-15 is a new marker for predicting death and HF in post-AMI patients. GDF-15 provides prognostic information over and above clinical factors and the established biomarker NT-proBNP. Combined levels of GDF-15 with NT-proBNP can identify a high-risk group of patients.

Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction

AIMSnMatrix metalloproteinase (MMP) activity is central to the development of left ventricular (LV) remodelling and dysfunction after acute myocardial infarction (AMI). We assessed the relationships with LV structure and function and outcome, of tissue inhibitors of metalloproteinase-1 (TIMP-1) and MMP-9, and compared with N-terminal pro-B-type natriuretic peptide (NTproBNP).nnnMETHODS AND RESULTSnWe studied 404 patients with AMI. Primary outcome measures were the associations of TIMP-1, MMP-9, and NTproBNP with death or heart failure, and with LV dimensions, function and remodelling (ΔLVEDV, change in LV end-diastolic volume between discharge and follow-up). Cut-off concentrations for prediction of death or heart failure were identified from receiver operator characteristic (ROC) curves. In multivariable analysis, TIMP-1 and NTproBNP had predictive value for LV ejection fraction pre-discharge (TIMP-1 P = 0.023; N-BNP P = 0.007) and at follow-up (TIMP-1 P = 0.001; N-BNP P = 0.003). MMP-9, TIMP-1, and NTproBNP correlated directly with LV volumes. MMP-9 (P = 0.005) and TIMP-1 (P = 0.036), but not NTproBNP, correlated with ΔLVEDV. For the combined endpoint of death or heart failure the area under the ROC curve was 0.640 for MMP-9, 0.799 for NTproBNP and 0.811 for TIMP-1. Patients with TIMP-1 > 135 ng/mL (P < 0.001) or NTproBNP >1472 fmol/mL (P < 0.001) had increased risk of endpoint. Consideration of both NTproBNP and TIMP-1 further improved risk stratification.nnnCONCLUSIONnTIMP-1 and MMP-9 correlate with echocardiographic parameters of LV dysfunction and remodelling after AMI and may identify patients at risk of subsequent LV remodelling and adverse prognosis.

C-Terminal Provasopressin (Copeptin) is Associated With Left Ventricular Dysfunction, Remodeling, and Clinical Heart Failure in Survivors of Myocardial Infarction

BACKGROUNDnAcute myocardial infarction (AMI) is associated with left ventricular (LV) dysfunction and clinical heart failure. Arginine vasopressin is elevated in heart failure and the C-terminal of provasopressin (Copeptin) is associated with adverse outcome post-AMI. The aim of this study was to describe the association between Copeptin with LV dysfunction, volumes, and remodeling and clinical heart failure post-AMI.nnnMETHODS AND RESULTSnWe studied 274 subjects with AMI. Copeptin was measured from plasma at discharge and subjects underwent echocardiography at discharge and follow-up (median 155 days). Subjects were followed for clinical heart failure for a median of 381 days. Remodeling was assessed as the change (Delta) in LV volumes between echo examinations. Copeptin correlated directly with wall motion index score (WMIS) and inversely with LV ejection fraction (LVEF) at discharge (WMIS, r=0.276, P < .001; LVEF, r=-0.188, P=.03) and follow-up (WMIS, r=0.244, P < .001; LVEF, r=-0.270, P < .001) and with ventricular volumes at follow-up (LVEDV, r=0.215, P=.002; LVESV, r=0.299, P < .001). Copeptin was associated with ventricular remodeling; DeltaEDV; r=0.171, P=0.015, DeltaESV; r=0.186, P=.008. Subjects with increasing LVESV had higher levels of Copeptin (median 6.30 vs. 5.75 pmol/L, P=.012). Subjects with clinical heart failure (n=30) during follow-up had higher Copeptin before discharge (median 13.55 vs. 5.80, P < .001). In a Cox proportional hazards model, Copeptin retained association with clinical heart failure. Kaplan-Meier assessment revealed increased risk in subjects with Copeptin >6.31 pmol/L.nnnCONCLUSIONSnCopeptin is associated with LV dysfunction, volumes, and remodeling and clinical heart failure post-AMI. Measurement of Copeptin may provide prognostic information and the AVP system may be a therapeutic target in post-MI LV dysfunction.

MicroRNA-150: A Novel Marker of Left Ventricular Remodeling After Acute Myocardial Infarction

Background—Left ventricular (LV) remodeling after acute myocardial infarction is associated with adverse prognosis. MicroRNAs (miRNAs) regulate the expression of several genes involved in LV remodeling. Our aim was to identify miRNAs associated with LV remodeling after acute myocardial infarction. Methods and Results—We studied 90 patients after first ST-segment–elevation acute myocardial infarction. A derivation cohort consisted of 60 patients characterized by echocardiography predischarge and at 6-month follow-up. Thirty patients characterized by magnetic resonance imaging predischarge and at 4-month follow-up were the validation cohort. Remodeling was defined as an increase in LV end-diastolic volume (&Dgr;EDV>0) between discharge and follow-up. Circulating miRNAs were measured by microarrays and polymerase chain reaction. Using a systems-based approach, we identified several miRNAs potentially involved in LV remodeling. In the derivation cohort, one of these miRNAs, miR-150, was downregulated in patients with remodeling (&Dgr;EDV>0) compared with patients without remodeling (&Dgr;EDV⩽0). In the validation cohort, patients with remodeling had 2-fold lower levels of miR-150 than those without (P=0.03). miR-150 outperformed N-terminal pro-brain natriuretic peptide to predict remodeling (area under the receiver-operating characteristic curve of 0.74 and 0.60, respectively). miR-150 reclassified 54% (95% confidence interval, 5–102; P=0.03) of patients misclassified by N-terminal pro-brain natriuretic peptide and 59% (95% confidence interval, 9–108; P=0.02) of patients misclassified by a multiparameter clinical model, including age, sex, and admission levels of troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide. Conclusions—Low circulating levels of miR-150 are associated with LV remodeling after first ST-segment–elevation acute myocardial infarction. miR-150 has potential as a novel biomarker in this setting.Background— Left ventricular (LV) remodeling after acute myocardial infarction is associated with adverse prognosis. MicroRNAs (miRNAs) regulate the expression of several genes involved in LV remodeling. Our aim was to identify miRNAs associated with LV remodeling after acute myocardial infarction.nnMethods and Results— We studied 90 patients after first ST-segment–elevation acute myocardial infarction. A derivation cohort consisted of 60 patients characterized by echocardiography predischarge and at 6-month follow-up. Thirty patients characterized by magnetic resonance imaging predischarge and at 4-month follow-up were the validation cohort. Remodeling was defined as an increase in LV end-diastolic volume (ΔEDV>0) between discharge and follow-up. Circulating miRNAs were measured by microarrays and polymerase chain reaction. Using a systems-based approach, we identified several miRNAs potentially involved in LV remodeling. In the derivation cohort, one of these miRNAs, miR-150, was downregulated in patients with remodeling (ΔEDV>0) compared with patients without remodeling (ΔEDV≤0). In the validation cohort, patients with remodeling had 2-fold lower levels of miR-150 than those without ( P =0.03). miR-150 outperformed N-terminal pro-brain natriuretic peptide to predict remodeling (area under the receiver-operating characteristic curve of 0.74 and 0.60, respectively). miR-150 reclassified 54% (95% confidence interval, 5–102; P =0.03) of patients misclassified by N-terminal pro-brain natriuretic peptide and 59% (95% confidence interval, 9–108; P =0.02) of patients misclassified by a multiparameter clinical model, including age, sex, and admission levels of troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide.nnConclusions— Low circulating levels of miR-150 are associated with LV remodeling after first ST-segment–elevation acute myocardial infarction. miR-150 has potential as a novel biomarker in this setting.

Myeloperoxidase aids prognostication together with N-terminal pro-B-type natriuretic peptide in high-risk patients with acute ST elevation myocardial infarction

Background: Inflammation plays a critical role in acute myocardial infarction (MI). One such inflammatory marker is myeloperoxidase (MPO). Its role as a predictor of death or MI in patients with ST segment elevation myocardial infarction (STEMI) is unclear. Aim: To investigate the role of MPO as a predictor of death or MI in patients with STEMI and to compare it with N-terminal pro-B-type natriuretic peptide (NT-BNP). Method: 384 post STEMI patients were studied. Patients were followed up for the combined end point of death or readmission with non-fatal MI. Results: There were 40 deaths and 37 readmissions with MI. Median MPO was raised in patients experiencing death or MI than in survivors (median (range), 50.6 (15.3–124.1) ng/ml vs 33.5 (6.6–400.2) ng/ml, pu200a=u200a0.001). Using a Cox proportional hazards model, log median MPO (HR 6.91, 95% CI 1.79 to 26.73, pu200a=u200a0.005) and log median NT-BNP (HR 4.21, 95% CI 1.53 to 11.58, pu200a=u200a0.005) independently predicted death or non-fatal MI. MPO had predictive power in both below and above median NT-BNP levels (log rank 5.60, pu200a=u200a0.020 and log rank 5.12, pu200a=u200a0.024, respectively). The receiver-operating curve for median NT-BNP yielded an area under the curve (AUC) of 0.72 (95% CI 0.65 to 0.79, p<0.001); for median MPO, the AUC was 0.62 (95% CI 0.55 to 0.69, pu200a=u200a0.001). The logistic model combining the two markers yielded an AUC of 0.76 (95% CI 0.69 to 0.82, p<0.001). Conclusion: MPO and NT-BNP may be useful tools for risk stratification of all acute coronary syndromes, including patients with STEMI at higher risk.

Plasma N-terminal B-Type natriuretic peptide as an indicator of long-term survival after acute myocardial infarction: comparison with plasma midregional pro-atrial natriuretic peptide: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.

OBJECTIVESnOur aim was to assess the prognostic value of midregional pro-atrial natriuretic peptide (MR-proANP) in patients after acute myocardial infarction (AMI).nnnBACKGROUNDnMultimarker strategies may assist risk stratification after AMI. Midregional pro-atrial natriuretic peptide is a newly described stable fragment of N-terminal pro-atrial natriuretic peptide. We compared the prognostic value of MR-proANP and an established marker, N-terminal pro-B-type natriuretic peptide (NT-proBNP), after AMI.nnnMETHODSnWe recruited 983 consecutive post-AMI patients (720 men, median age 65 [range 24 to 95] years) in a prospective study with follow-up over 343 (range 0 to 764) days.nnnRESULTSnPlasma MR-proANP was raised in patients who died (n = 101) compared with that seen in survivors (median 310 [range 48 to 1,150] pmol/l vs. 108 [range 4.9 to 1,210] pmol/l, p < 0.0001). Using Cox modeling, log(10)MR-proANP (hazard ratio 3.87) and log(10)NT-proBNP (hazard ratio 3.25) were significant independent predictors of death. In patients stratified by NT-proBNP in the highest quartile (> approximately 5,900 pmol/l), MR-proANP in the top quartile ( approximately 330 pmol/l) was associated with poorer outcome (p < 0.0001). Findings were similar for heart failure as an individual end point. However, neither marker predicted recurrent AMI.nnnCONCLUSIONSnThe A- and B-type natriuretic systems are activated after AMI. Midregional pro-atrial natriuretic peptide is a powerful predictor of adverse outcome, especially in those with an elevated NT-proBNP. Midregional pro-atrial natriuretic peptide may represent a clinically useful marker of prognosis after an AMI as part of a multimarker strategy targeting the natriuretic neurohormonal pathway.

Circulating Stromelysin-1 (MMP-3): A novel predictor of LV dysfunction, remodelling and all-cause mortality after acute myocardial infarction

Changes to cardiac matrix are central to ventricular remodelling after acute MI and matrix metalloproteinase expression is implicated in this process. We investigated the temporal profile of MMP‐3 and its relationship to LV dysfunction and prognosis following AMI.

N-terminal pro B type natriuretic peptide complements the GRACE risk score in predicting early and late mortality following acute coronary syndrome

The GRACE (Global Registry of Acute Coronary Events) risk score has been shown to offer predictive power with regard to death and AMI (acute myocardial infarction) in patients with ACS (acute coronary syndromes). NT-proBNP (N-terminal pro-B-type natriuretic peptide) has also been found to be useful in predicting mortality following ACS. In the present study, we sought to investigate the use of the GRACE score and NT-proBNP levels at predicting risk of early and late deaths following ACS. We studied 1033 patients (740 men, mean age 66.5+/-12.7 years) with AMI. Blood was drawn once within 24 h following the onset of chest pain. The plasma concentration of NT-proBNP was determined using an in-house non-competitive immunoassay. Patients were GRACE risk scored. The 30-day mortality was 3.7% and the 6-month mortality was 7.8%, and all were related to higher GRACE risk scores (P=0.001 for trend). Higher NT-proBNP levels were also related to increased mortality (P<0.0001). In a Cox proportional hazards model, independent predictors of 30-day and 6-month mortality included NT-proBNP levels and the GRACE risk score. The receiver-operating curve for the GRACE risk score was complemented by NT-proBNP levels for prediction of 30-day mortality [AUC (area under the curve), 0.85] and 6-month mortality (AUC, 0.81). NT-proBNP gives complementary information to the GRACE risk score for predicting early and late mortality. The inclusion of the NT-proBNP blood test is useful in risk-stratifying patients after ACS.

Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers?

BACKGROUNDnSoluble ST2 is a marker of cellular stress and injury whose natural ligand is interleukin-33. We investigate, for the first time, the relationship of IL-33 and ST2 with death at 30-days, 1-year and beyond in unselected STEMI patients. We assess the incremental value they offer over GRACE score and NT-proBNP. Secondary endpoints were heart failure readmission and re-infarction.nnnMETHODSnST2 and IL-33 were measured in 677 patients 3-5 days after admission. Median follow-up was 587 (134-2818) days during which 101 (15%) patients died.nnnRESULTSnST2 was higher in those who died when compared to event-free survivors (median [range] 1125 [123-15781] vs. 630 [59-11729] pg/ml, p<0.001) as was IL-33 (75 [5.4-17893] vs. 5.4 [5.4-16466] pg/mL, p=0.006). Multivariate Cox regression analysis reveals that elevated ST2 is associated with increased risk of mortality at 30-days (HR 9.34, p<0.001) and 1-year (HR 3.15, p=0.001). These relationships continued after further adjustment for GRACE-RS and NT-proBNP. Combining ST2 (c-statistic 0.82, p<0.001), GRACE-RS (0.82, p<0.001) and NT-proBNP (0.84, p<0.001) leads to a significant improvement in the c-statistic for 30-day mortality to 0.90 (p=0.01). IL-33 above 5.4 pg/ml was independently associated with increased mortality at 30-days (HR 4.16, p=0.007) and 1-year (HR 2.29, p=0.008) but, did not add incremental prognostic value over using GRACE-RS and NT-proBNP. The ratio IL-33/ST2 was not associated with events.nnnCONCLUSIONSnElevated ST2 and IL-33 were both associated with increased mortality. ST2 demonstrated incremental value over contemporary risk markers but, IL-33 did not. ST2 has a potential role in risk stratification using a multi-marker approach.

Usefulness of Plasma Tissue Inhibitors of Metalloproteinases as Markers of Prognosis After Acute Myocardial Infarction

Alterations in the balance of matrix metalloproteinase to tissue inhibitor of metalloproteinase (TIMP) are seen after acute myocardial infarction (AMI) and are associated with adverse left ventricular remodeling and prognosis in this setting. We aimed to investigate the association between TIMP levels and the occurrence of major adverse cardiac events (MACEs) after AMI. We measured plasma TIMP-1, -2, and -4 levels in 1,313 patients presenting with AMI. Subjects were followed over a median period of 520 days for the occurrence of MACEs. Clinical risk was assessed using the Global Registry of Acute Coronary Events (GRACE) score. All TIMP levels correlated with patient age and inversely with estimated glomerular filtration rate (all p values <0.001). Levels were higher in women versus men (p <0.001) and in subjects with a history of diabetes (TIMP-1, p <0.001; TIMP-2, p = 0.002; TIMP-4, p <0.001) or hypertension (TIMP-1, p = 0.031; TIMP-2, p <0.001; TIMP-4, p <0.001). TIMP-1 and TIMP-4 were higher in subjects with previous MI or angina (p <0.001). TIMP levels increased incrementally with quartiles of GRACE score (p <0.001). All TIMPs showed univariate association with the occurrence of MACEs (p <0.001). Areas under the receiver operator characteristic curve for prediction of MACE at 1 year were 0.61 for TIMP-1, 0.57 for TIMP-2, and 0.64 for TIMP-4. Combination of TIMPs with GRACE risk score revealed a greater area under the curve than GRACE score alone (0.72 vs 0.69, p = 0.0015). On multivariable Cox proportional hazards analysis, GRACE score (p <0.001) and plasma TIMPs (log TIMP-1, p = 0.017; log TIMP-2, p <0.001; log TIMP-4, p = 0.011) independently predicted MACEs. Using Kaplan-Meier analysis, the risk of MACEs increased incrementally with the number of TIMPs above their respective median (p <0.001 for all comparisons, log-rank test). In conclusion, higher plasma TIMP-1, -2, and -4 after AMI are associated with MACEs and provide additional prognostic information to that obtained from GRACE clinical risk scores alone.