Hafid Narayan

Interleukin 33 and ST2 in non–ST-elevation myocardial infarction: Comparison with Global Registry of Acute Coronary Events Risk Scoring and NT-proBNP

BACKGROUND Soluble ST2 is a marker of biomechanical strain for which the natural ligand is interleukin 33 (IL-33). They have not been studied together in non-ST-elevation myocardial infarction (NSTEMI). We investigated their relationship with death, heart failure (HF) readmission, and reinfarction combined (termed major adverse cardiac events [MACE]) and, separately, in unselected patients using Global Registry of Acute Coronary Events Risk Scoring (GRACE-RS) and n terminal pro B type natriuretic peptide (NT-proBNP) as benchmark comparators. METHODS ST2 and IL-33 were measured in 577 patients 3 to 5 days after admission. Mean follow-up was 532 (150-1059) days, during which 156 patients (27%) reached the primary end point. RESULTS ST2 was higher in those who experienced MACE when compared with event-free survivors (median 782 pg/mL vs 596, P < .001), but there was no difference in IL-33 levels across any end point. Multivariate Cox regression analysis reveals that elevated ST2 is independently associated with increased risk of MACE during the long term (hazard ratio [HR] 2.01, P = .005). This relationship continues on further adjustment for either GRACE risk score or NT-proBNP individually but not on adjustment for both. ST2 also independently predicts reinfarction (HR 2.48, P = .03) and 30-day mortality (HR 4.43, P = .02, c-statistic 0.73, P < .001). Adding ST2 to GRACE or to NT-proBNP did not lead to significant improvements in the c-statistic for MACE for long-term follow-up (P = .27 and P = .57, respectively) or the net reclassification index. Neither IL-33 nor its ratio with ST2 was associated with study end points. CONCLUSIONS Elevated ST2 predicts adverse outcome in non-ST-elevation myocardial infarction but does not significantly improve risk stratification for established markers. Interleukin 33 was not related to adverse events.

Prognostic value of mid-regional pro-adrenomedullin levels taken on admission and discharge in non-ST-elevation myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) II study.

OBJECTIVES The purpose of this study was to assess the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non-ST-elevation myocardial infarction (MI) and identify values to aid clinical decision making. N-terminal pro-B-type natriuretic peptide and GRACE (Global Registry of Acute Coronary Events) score were used as comparators. BACKGROUND sAM is a stable precursor of adrenomedullin. METHODS We measured plasma sAM on admission and discharge in 745 non-ST-elevation MI patients (514 men, median age 70.0 +/- 12.7 years). The primary end point was a composite of death, heart failure, hospitalization, and recurrent acute MI over mean follow-up of 760 days (range 150 to 2,837 days), with each event assessed individually as secondary end points. RESULTS During follow-up, 120 (16.1%) patients died, and there were 65 (8.7%) hospitalizations for heart failure and 77 (10.3%) recurrent acute MIs. Both admission and discharge levels were increased (median 0.81 nmol/l [range 0.06 to 5.75 nmol/l] and 0.76 nmol/l [range 0.25 to 6.95 nmol/l], respectively) compared with established normal ranges. Multivariate adjusted Cox regression models revealed that both were associated with the primary end point (hazard ratio: 9.75 on admission and 7.54 on discharge; both p < 0.001). Admission sAM was particularly associated with early (<30 days) mortality (c-statistic = 0.90, p < 0.001), and when compared with N-terminal pro-B-type natriuretic peptide and GRACE score, it was the only independent predictor of this end point. Admission sAM >1.11 nmol/l identified those at highest risk of death (p < 0.001). Patients with above-median admission sAM may benefit from revascularization. CONCLUSIONS sAM level is prognostic for death or heart failure. Admission levels are a strong predictor of early mortality and, when >1.11 nmol/l, complements the GRACE score to improve risk stratification.

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.

C-terminal provasopressin (copeptin) as a prognostic marker after acute non-ST elevation myocardial infarction: Leicester Acute Myocardial Infarction Peptide II (LAMP II) study.

Copeptin, the 39-amino-acid C-terminal portion of provasopressin, has been shown to be an independent predictor for adverse events following STEMI (ST elevation myocardial infarction). We hypothesized that plasma copeptin was an independent predictor for adverse outcomes following acute NSTEMI (non-STEMI) and evaluated whether copeptin added prognostic information to the GRACE (Global Registry of Acute Coronary Events) score compared with NT-proBNP (N-terminal pro-B-type natriuretic peptide). Plasma copeptin and NT-proBNP were measured in 754 consecutive patients admitted to the hospital with chest pain and diagnosed as having NSTEMI in this prospective observational study. The end point was all-cause mortality at 6 months. Upper median levels of copeptin were strongly associated with all-cause mortality at 6 months. Copeptin was a significant predictor of time to mortality {HR (hazard ratio), 5.98 [95% CI (confidence interval, 3.75-9.53]; P < 0.0005} in univariate analysis and remained a significant predictor in multivariate analysis [HR, 3.03 (05% CI, 1.32-6.98); P = 0.009]. There were no significant differences between the area under ROC (receiver operating characteristic) curves of copeptin, NT-proBNP and the GRACE score. Copeptin improved accuracy of risk classification when used in combination with the GRACE score as determined by net reclassification improvement, whereas NT-proBNP did not. The relative utility of the GRACE score was increased more by copeptin than by NT-proBNP over a wide range of risks. Plasma copeptin is elevated after NSTEMI, and higher levels are associated with worse outcomes. Copeptin used in conjunction with the GRACE score improves risk stratification enabling more accurate identification of high-risk individuals.

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?

BACKGROUND Soluble 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. METHODS ST2 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. RESULTS ST2 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. CONCLUSIONS Elevated 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.

Matrix Metalloproteinase-2 predicts mortality in patients with acute coronary syndrome.

The aim of the present study was to investigate the predictive value of MMP (matrix metalloproteinase)-2, MMP-3 and MMP-9 levels in patients with acute coronary syndrome for death, readmission with HF (heart failure) or recurrent MI (myocardial infarction) and to compare them with established markers, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the GRACE (Global Registry of Acute Coronary Events) score. A single blood test was taken 4 days after admission in 1024 consecutive patients with acute MI with end points observed over 519 (134-1059) days [value is median (range)]. MMP-2 and MMP-3 were increased in patients who died (n=111) compared with survivors (P<0.006 and P=0.01 respectively), but were similar in patients with HF (n=106) or MI (n=138). MMP-9 levels were similar across study end points. Using Cox proportional hazards modelling, MMP-2 demonstrated an independent prediction of death [HR (hazard ratio) 6.60, P=0.001], along with NT-proBNP (HR 4.62, P<0.001) and the GRACE score (HR 1.03, P<0.001), but MMP-3, MMP-9 or log10-troponin I did not. For 1 year mortality, the areas under the receiver operating characteristic curves were 0.60 and 0.58 for MMP-2 and MMP-3 respectively, compared with 0.82 for NT-proBNP and 0.84 for the GRACE score (all P<0.001). Kaplan-Meier analysis revealed that MMP-2 levels in the top quartile were associated with higher mortality rates (log rank 12.49, P=0.006). On univariate analysis, MMP-2 and MMP-3 had a weak association with HF readmission, which was lost after adjustment for clinical factors. None of the MMPs tested predicted MI. In conclusion, this is the first single centre study that identifies MMP2 as an independent predictor of all-cause mortality post-ACS (acute coronary syndrome); however, NT-proBNP and the GRACE score are superior for risk stratification in this cohort.

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.

Proteinase 3 and prognosis of patients with acute myocardial infarction

A multimarker approach may be useful for risk stratification in AMI (acute myocardial infarction) patients, particularly utilizing pathways that are pathophysiologically distinct. Our aim was to assess the prognostic value of PR3 (proteinase 3) in patients post-AMI. We compared the prognostic value of PR3, an inflammatory marker, with an established marker NT-proBNP (N-terminal pro-B-type natriuretic peptide) post-AMI. We recruited 900 consecutive post-AMI patients (700 men; age, 64.6±12.4 years) in a prospective study with follow-up over 347 (0–764) days. Plasma PR3 was significantly higher in patients who died [666.2 (226.8–4035.5) ng/ml; P<0.001] or were readmitted with heart failure [598 (231.6–1803.9) ng/ml, P<0.004] compared with event-free survivors [486.9 (29.3–3118.2) ng/ml]. Using Cox modelling, log10 PR3 [HR (hazard ratio), 3.80] and log10 NT-proBNP (HR, 2.51) were significant independent predictors of death or heart failure. When patients were stratified by plasma NT-proBNP (median, 1023 pmol/l), PR3 gave additional predictive value for death or heart failure, in both the patients in whom NT-proBNP level was above the median (log rank for trend, 12.54; P<0.0004) and those with NT-proBNP level below the median (log rank for trend, 3.83; P<0.05). Neither marker predicted recurrent AMI. In conclusion, this is the first report showing a potential role for the serine protease PR3 in determining mortality and incidence of heart failure following AMI, independent of established conventional risk factors. PR3 may represent a clinically useful marker of prognosis after an AMI as part of a multimarker strategy.

Pro-substance p for evaluation of risk in acute myocardial infarction.

BACKGROUND Pro-substance P (ProSP) is a stable surrogate marker for labile substance P, which has pro-inflammatory effects, increases platelet aggregation and clot strength, and reduces fibrinolysis. OBJECTIVES This study assessed whether ProSP was associated with poor prognosis after acute myocardial infarction (AMI) to identify novel pathophysiological mechanisms. METHODS ProSP was measured in 1,148 AMI patients (825 men, mean age 66.2 ± 12.8 years). Endpoints were major adverse cardiac events (composite of death, reinfarction, and heart failure [HF] hospitalization), death/reinfarction, and death/HF. GRACE (Global Registry of Acute Coronary Events) scores were compared with ProSP for death and/or reinfarction at 6 months. RESULTS During 2-year follow-up, there were 140 deaths, 112 HF hospitalizations, and 149 re-AMI. ProSP levels were highest on the first 2 days after admission and related to estimated glomerular filtration rate, age, history of diabetes, ischemic heart disease or hypertension, Killip class, left ventricular wall motion index, and sex. Multivariate Cox regression models showed ProSP level was a predictor of major adverse events (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.10 to 1.54; p < 0.002), death and/or AMI (HR: 1.42; 95% CI: 1.20 to 1.68; p < 0.0005), death and/or HF (HR: 1.38; 95% CI: 1.14 to 1.67; p < 0.001). ProSP levels with GRACE scores were independent predictors of 6-month death and/or reinfarction (p < 0.0005 for both). ProSP-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement of 31.6 (95% CI: 14.3 to 49.0; p < 0.0005) mainly by down-classifying those without endpoints. CONCLUSIONS ProSP levels post-AMI are prognostic for death, recurrent AMI, or HF, and they improve risk prediction of GRACE scores, predominantly by down-classifying risk in those without events.

Activation of a novel natriuretic endocrine system in humans with heart failure.

Proguanylin and prouroguanylin are the inactive precursors of guanylin and uroguanylin, natriuretic peptides involved in the regulation of sodium balance. Urinary uroguanylin levels have been found previously to be elevated in patients with HF (heart failure). The aim of the present study was to investigate whether plasma proguanylin and prouroguanylin levels are increased in patients with HF and to evaluate their relationship with cardiac and renal function. In this prospective observational study, we recruited 243 patients with HF (151 men) and 72 healthy controls. In patients with HF, plasma levels of proguanylin [median, 7.2 (range, 0.9–79.0) μg/l] and prouroguanylin [8.3 (1.7–53.0 μg/l)] were both significantly (P<0.0005) higher compared with levels in healthy controls [5.5 (0.4–22.3 μg/l) for proguanylin and 6.3 (2.5–16.9) μg/l for prouroguanylin]. In patients with HF, increased age, a history of hypertension, diabetes and atrial fibrillation, use of diuretics, a higher NYHA (New York Heart Association) class and a lower eGFR (estimated glomerular filtration rate) were significant univariate predictors of proguanylin and prouroguanylin levels. In multivariate analysis, a history of hypertension and low eGFR both had strong independent associations with proguanylin and prouroguanylin levels. Proguanylin and prouroguanylin varied significantly between NYHA class with a trend of increasing plasma concentrations with worsening severity of symptoms. In conclusion, plasma proguanylin and prouroguanylin are elevated in patients with HF. Elevated plasma proguanylin and prouroguanylin levels are associated with hypertension, renal impairment and increasing severity of HF. This novel endocrine system may contribute to the pathophysiology of HF.