Proenkephalin and prognosis in heart failure with preserved ejection fraction: a GREAT network study.

BACKGROUND: Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction. METHODS: In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies. RESULTS: PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1-132.0]) compared to normal controls (56.3 [47.9-70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e' (rs 0.635, - 0.741, - 0.275, 0.476, respectively, p < 0.0005). During 2 years follow-up 144 patients died and 220 had death/HF endpoints. Multivariable Cox regression models showed PENK independently predicted 2 year death/HF [hazard ratio (for 1 SD increment of log-transformed biomarker) HR 1.45 [95% CI 1.12-1.88, p = 0.005]], even after adjustment for troponin (HR 1.59 [1.14-2.20, p = 0.006]), and Body Mass Index (HR 1.63 [1.13-2.33, p = 0.009]). PENK showed no interaction with ejection fraction status for prediction of poor outcomes. Net reclassification analyses showed PENK significantly improved classification of death/HF outcomes for multivariable models containing natriuretic peptide, troponin and Body Mass Index (p < 0.05 for all). CONCLUSIONS: In HFpEF, PENK levels are related to BMI, and measures of diastolic dysfunction and are prognostic for all-cause mortality and heart failure rehospitalisation.

Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study.

BACKGROUND: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis. OBJECTIVES: This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome. METHODS: This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 µmol/l or 50% higher than the admission value within 5 days of presentation. RESULTS: During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively. CONCLUSIONS: PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.

Growth hormone for risk stratification and effects of therapy in acute myocardial infarction.

CONTEXT: Excess growth hormone (GH) is associated with early mortality. OBJECTIVES: We assessed the association of GH with prognosis after acute myocardial infarction (AMI), and the effects of secondary prevention therapies. METHODS: GH was measured using a high-sensitivity assay in 953 AMI patients (687 males, mean age 66.1 ± 12.8 years). RESULTS: During 2 years follow-up, there were 281 major adverse cardiac events (MACE). Patients with MACE had higher GH levels (median [range], 0.91 [0.04-26.28] µg/L) compared to event-free survivors (0.59 [0.02-21.6], p < 0.0005). In multivariate Cox survival analysis, GH was a significant predictor of MACE (hazard ratios 1.43, p = 0.026 and 1.49, p = 0.01, respectively) with significant interactions with beta blocker therapy (p = 0.047) and angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACE/ARB) therapy (p = 0.016). CONCLUSIONS: GH levels post-AMI are prognostic for MACE and may indicate those patients who benefit from beta blocker and ACE/ARB therapy.

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.

Proenkephalin and prognosis after acute myocardial infarction.

OBJECTIVES: The goal of this research was to assess the prognostic value of proenkephalin (PENK) levels in acute myocardial infarction (AMI) by using N-terminal pro-B-type natriuretic peptide and Global Registry of Acute Coronary Events (GRACE) scores as comparators and to identify levels that might be valuable in clinical decision making. BACKGROUND: PENK is a stable analyte of labile enkephalins. Few biomarkers predict recurrent AMI. METHODS: We measured PENK in 1,141 patients (820 male subjects; mean age 66.2 ± 12.8 years) with AMI. Endpoints were major adverse events (composite of death, myocardial infarction [MI], and heart failure [HF] hospitalization) and recurrent MI at 2 years. GRACE scoring was used for comparisons with PENK for the death and/or MI endpoint at 6 months. RESULTS: During follow-up, 139 patients died, and there were 112 HF hospitalizations and 149 recurrent AMIs. PENK levels were highest on admission and were related to estimated glomerular filtration rate, left ventricular wall motion index, sex, blood pressure, and age. Multivariable Cox regression models found that the PENK level was a predictor of major adverse events (hazard ratio [HR]: 1.52 [95% confidence interval (CI): 1.19 to 1.94]), death and/or AMI (HR: 1.76 [95% CI: 1.34 to 2.30]), and death and/or HF (HR: 1.67 [95% CI: 1.24 to 2.25]) (all comparisons p < 0.001), as well as recurrent AMI (HR: 1.43 [95% CI: 1.07 to 1.91]; p < 0.01). PENK levels were independent predictors of 6-month death and/or MI compared with GRACE scores. PENK-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement [>0] of 21.9 [95% CI: 4.5 to 39.4]; p < 0.014). PENK levels <48.3 pmol/l and >91 pmol/l detected low- and high-risk patients, respectively. CONCLUSIONS: PENK levels reflect cardiorenal status post-AMI and are prognostic for death, recurrent AMI, or HF. Cutoff values define low- and high-risk groups and improve risk prediction of GRACE scores.

Vitamin D and prognosis in acute myocardial infarction.

BACKGROUND: Vitamin D status (VDS) has been linked to mortality and incident acute myocardial infarction (AMI) in healthy cohorts. Associations with recurrent adverse cardiovascular events in those with cardiovascular disease are less clear. Our objective was to assess the prevalence and prognostic impact of VDS on patients presenting with AMI. METHODS: We measured plasma 25-(OH)D3 and 25-(OH)D2 using isotope dilution tandem mass spectrometry, in 1259 AMI patients (908 men, mean age 65.7 ± 12.8 years). The primary endpoint was major adverse events (MACE), a composite of death (n=141), heart failure hospitalisation (n=111) and recurrent AMI (n=147) over median follow-up of 550 days (range 131-1095). Secondary endpoints were fatal and non-fatal MACE. RESULTS: Almost 74% of the patients were vitamin D deficient (<20 ng/ml 25-(OH)D). Plasma 25-(OH)D existed mainly as 25-(OH)D3 which varied with month of recruitment. Multivariable survival Cox regression models stratified by recruitment month (adjusted for age, gender, past history of AMI/angina, hypertension, diabetes, hypercholesterolaemia, ECG ST change, Killip class, eGFR, smoking, plasma NTproBNP), showed 25-(OH)D3 quartile as an independent predictor of MACE(P<0.001) and non-fatal MACE(P<0.01), but not death. Using the lowest 25-(OH)D3 quartile(<7.3 ng/ml) as reference for MACE prediction, the 2nd, 3rd and 4th quartiles showed significantly lower hazard ratios (HR 0.59(P<0.002), 0.58(P<0.001), and 0.59(P<0.003) respectively). For non-fatal MACE prediction, the 2nd, 3rd and 4th 25-(OH)D3 quartiles were all significantly different from the lowest reference quartile (HR 0.69(P<0.05), 0.54(P<0.003) and 0.59(P<0.014) respectively). CONCLUSIONS: VDS is prognostic for MACE (predominantly non-fatal MACE) post-AMI, with approximate 40% risk reduction for 25-(OH)D3 levels above 7.3 ng/ml.

Differences in performance of five types of aortic valve prostheses: haemodynamic assessment by dobutamine stress echocardiography.

BACKGROUND: In patients being considered for aortic valve replacement, there remains controversy over which design or tissue offers the best performance. We aimed to evaluate in a single study the haemodynamic performances of five different widely used aortic valve prostheses: stentless porcine xenograft (Elan), stentless bovine pericardium (Pericarbon Freedom), stented porcine xenograft (Aspire), stented bovine pericardium (More) and mechanical (Ultracor). We also compared them with normal aortic valves and stenosed valves of variable severity. METHODS AND RESULTS: Preoperative echocardiography and dobutamine stress echocardiography at 1 year postoperatively were undertaken in 106 patients (n=18-24 from each group). Stentless bioprostheses, whether porcine or bovine, displayed superior haemodynamics across nearly all echocardiographic parameters: lower gradients, larger effective orifice area, higher dimensionless severity index (DSI) and lower resistance, when compared with stented or mechanical prostheses. Comparing both stented designs, bovine tissue performed the worst at rest, but with stress, there was no difference. The stress performances of the stentless bioprostheses were similar to the mildly stenosed native aortic valve, whereas the performances of the stented and mechanical prostheses resembled that of native valves with mild-to-moderate stenoses. Haemodynamic differences, however, did not translate into differences in left ventricular mass reduction at 1 year. CONCLUSIONS: Stentless bioprostheses displayed haemodynamics superior to stented or mechanical prostheses and had the closest performance to a normal, native aortic valve. Stress DSI data, least reliant on variable annulus/valve sizes and flow rates, provided the best haemodynamic discrimination.

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.

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.

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.

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.

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.

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.

Procalcitonin as a prognostic marker in patients with acute myocardial infarction.

BACKGROUND: Procalcitonin is involved in the inflammatory response and is associated with adverse prognosis in certain conditions. AIMS: To investigate the association between procalcitonin and major adverse cardiac events (MACE), left ventricular (LV) function and remodelling following acute myocardial infarction (AMI). METHODS: Plasma procalcitonin was measured in 977 patients with AMI. Subjects were followed for MACE (median 671 days). A subgroup underwent echocardiography at discharge and follow-up LV function and volume assessment. RESULTS: Procalcitonin was associated with MACE on uni- and multivariable analysis. Kaplan-Meier assessment revealed an adverse outcome in subjects with procalcitonin above the median. Procalcitonin was related to markers of LV dysfunction and remodelling. CONCLUSION: Procalcitonin is associated with MACE, LV dysfunction and remodelling post-AMI.

The midregional portion of proadrenomedullin is an independent predictor of left ventricular mass index in hypertension.

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease. Elevated natriuretic peptides in LVH have spurred interest that biomarkers may play a role in screening programs. Adrenomedullin (ADM) is a 52-amino acid peptide mediating vasorelaxation, natriuresis, and diuresis. The midregional portion of proADM (MRproADM) is secreted stoichiometrically with ADM; hence, it can be used as a surrogate marker of ADM. We compared the diagnostic performance of MRproADM for the detection of LVH with N-terminal pro-B-type natriuretic peptide (NTproBNP). Two hundred fifty-three hypertensive patients were derived from a local screening study. The MRproADM and NTproBNP levels were assayed using immunoluminometric assays. The MRproADM levels were significantly elevated in patients with LVH than those without (mean [SD]: 0.73 [0.25] vs 0.59 [0.18] nmol/L, P < .001). In multivariate analyses, male sex (P < .001) and log MRproADM (P = .003) retained significance for detecting LVH. Receiver operating characteristic curve for MRproADM yielded an area under the curve of 0.71; confidence interval, 0.62-0.81; P < .001, superior to NTproBNP. An optimal cutoff value for MRproADM as an indicator of LVH was 0.50 nmol/L, with a sensitivity, specificity, and negative predictive value of 90.5%, 36.5%, and 95.1%, respectively. The high negative predictive value of the MRproADM assay allows it to be used as a rule-out test for LVH when stratifying patients into high or low risk. Patients who test positive would necessitate echocardiography, enabling better resource allocation.

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) microg/l] and prouroguanylin [8.3 (1.7-53.0 microg/l)] were both significantly (P<0.0005) higher compared with levels in healthy controls [5.5 (0.4-22.3 microg/l) for proguanylin and 6.3 (2.5-16.9) microg/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.

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.

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

AIMS: Our 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). METHODS AND RESULTS: We 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). CONCLUSION: Growth 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.

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.

Gender and renal function influence plasma levels of copeptin in healthy individuals.

The present study sought to identify confounding factors for the interpretation of copeptin levels in healthy individuals. The natriuretic peptides are recognized as diagnostic and prognostic tools in HF (heart failure). Interpretation of BNP (brain natriuretic peptide) and NTproBNP (N-terminal pro-BNP) levels is multifaceted as their secretion is influenced by many variables. A newly identified glycopeptide called copeptin is comparable with the natriuretic peptides in the diagnosis and prognosis of HF and as a prognostic biomarker after AMI (acute myocardial infarction). Copeptin, derived from the C-terminal portion of the precursor to AVP (arginine vasopressin), is secreted stoichiometrically with vasopressin, hence it can be used as a surrogate marker of the AVP system. In the present study, 706 healthy volunteers were recruited from a local HF screening study. Participants with a history of cardiovascular disease and those with echocardiographic abnormalities were excluded from the study. Copeptin and NTproBNP levels were assayed using in-house immunoluminometric assays. Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4-44.3) compared with 3.2 (1.0-14.8) pmol/l; P<0.001]. In males, copeptin was correlated with eGFR (estimated glomerular filtration rate; r(s)=-0.186, P<0.001). In females, the correlation of copeptin with eGFR was weak (r(s)=-0.097, P=0.095). DT (deceleration time) and left atrial size correlated with higher copeptin levels (r(s)=0.085, P=0.029 and r(s)=0.206, P<0.001 respectively). Only gender (P<0.001), eGFR (P<0.001), left atrial size (P=0.04) and DT (P=0.02) remained independently predictive of plasma copeptin. The present study suggests that gender and renal function specific partition values should be used to interpret copeptin values in future studies of this biomarker in HF or ischaemic heart disease.