The incremental prognostic and clinical value of multiple novel biomarkers in heart failure.

AIMS: In recent years there has been an increase in the number of biomarkers in heart failure (HF). The clinical role for these novel biomarkers in combination is not clear. METHODS AND RESULTS: The following novel biomarkers were measured from 628 patients recently hospitalized with decompensated HF; mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin, high-sensitivity cardiac troponin T (hs-cTnT), ST2, galectin-3, cystatin C, combined free light chains (cFLC) and high sensitivity C-reactive protein (hsCRP). The incremental prognostic value of these novel biomarkers was evaluated within an extensive model containing established predictors of mortality. During a mean (SD) follow-up of 3.2 (1.5) years, 290 (46%) patients died. Elevated concentrations of all novel biomarkers were associated with an increased unadjusted risk of mortality but only two-thirds were independent predictors following multivariable analysis. Using dichotomized cut-points from receiver operating characteristic analysis, MR-proADM, hs-cTnT, cFLC, hsCRP, and ST2 remained independent predictors of mortality. Further dichotomization into low (0-2 elevated biomarkers) or high (at least three of the five biomarkers elevated) risk groups provided greatest incremental prognostic value (hazard ratio 2.20, 95% confidence interval 1.37-3.54; P = 0.001) and improved the performance of the model (C-statistic 0.730 from 0.721, net reclassification index 32.5%). CONCLUSION: The novel biomarkers included in this study added little, if any, incremental prognostic value on their own to a model containing established predictors of mortality. However, following dichotomization, five of the novel biomarkers provided incremental prognostic value. There was a clear gradient in the risk of death with increasing numbers of elevated novel biomarkers, with the presence of at least three identifying patients at greatest risk of mortality.

Combined Free Light Chains Are Novel Predictors of Prognosis in Heart Failure.

OBJECTIVES: This study investigated the prevalence and potential incremental prognostic value of combined free light chains (cFLCs) in patients recently hospitalized with decompensated heart failure (HF). BACKGROUND: Inflammatory pathways are recognized in the pathogenesis and progression of HF. Free light chain (FLC) elevation is conventionally associated with monoclonal gammopathies, including multiple myeloma. Polyclonal increases in both kappa and lambda FLCs occur in autoimmune and other chronic inflammatory conditions. Recently, a novel assay for measuring kappa and lambda immunoglobulin FLCs together, known as combined free light chain (cFLC) has been developed. METHODS: Six hundred twenty-eight patients recently hospitalized with decompensated HF were studied. cFLCs were measured by turbidimetry using an immunoassay. The incremental prognostic value of cFLCs for mortality was evaluated using Cox proportional hazard models including 22 established predictors of outcome in HF. RESULTS: Of 628 patients, 290 (46%) died during a follow-up of 3.2 ± 1.5 years. Two hundred seventy patients (43%) had elevated cFLCs. There was a clear gradient in the risk of death according to cFLC quartile, with those in the top quartile having an unadjusted risk of mortality more than twice that of those in the lowest quartile (hazard ratio: 2.38; p < 0.0001). After multivariable analysis, cFLC remained an independent predictor of mortality, with an almost 50% higher adjusted risk for those in the top compared with bottom quartile. Older age, lower body mass index, New York Heart Association classification III/IV, previous myocardial infarction, current smoking and B-type natriuretic peptide, bilirubin, high-sensitivity C-reactive protein, glycated hemoglobin, and lymphocyte concentrations were also independent predictors of mortality. CONCLUSIONS: cFLCs are an independent predictor of mortality in patients recently hospitalized with decompensated HF. Further work is required to assess the effects of HF therapies on cFLC concentrations and whether or not directly targeting this marker of inflammation improves prognosis for patients with HF.

Spectral microvolt T-wave alternans testing has no prognostic value in patients recently hospitalized with decompensated heart failure.

AIMS: Microvolt T-wave alternans (MTWA) testing identifies beat-to-beat fluctuations in T-wave morphology, which have been linked to ventricular arrhythmias. However, clinical studies have produced conflicting results and data in heart failure (HF) have been limited. The aim of this study was to determine the prevalence and incremental prognostic value of spectral MTWA testing in an unselected cohort of patients recently hospitalized with HF. METHODS AND RESULTS: Consecutive admissions with confirmed HF were recruited, and survivors were invited to attend 1 month post-discharge for MTWA testing. A total of 648 of 1003 enrolled patients returned for MTWA testing (58% male, mean age 71 years). Forty-nine per cent were ineligible due to AF, pacemaker dependency, or inability to exercise. Of the 330 MTWA test results, 30% were positive, 24% negative, and 46% indeterminate. Overall, 268 deaths occurred during a median follow-up of 3.1 (interquartile range 1.9-3.9) years. Of the ineligible patients, 48% died vs. 35% of eligible patients (P < 0.001). Of those patients with positive, negative, and indeterminate tests, 27, 35, and 40%, respectively, died (P = 0.12). Even when analysed as non-negative (positive/indeterminate) vs. negative, there was still no between-group difference in mortality (P = 0.95). MTWA results categorized as positive, negative, or indeterminate showed no incremental prognostic value in a multivariable model, which included BNP. Paradoxically, when compared in a binary fashion with a non-negative result, a negative test was an independent predictor of death, as was ineligibility for MTWA testing. CONCLUSION: Spectral MTWA testing was not widely applicable and failed to predict mortality, and so cannot be endorsed as a risk stratification tool in HF.

Profile of microvolt T-wave alternans testing in 1003 patients hospitalized with heart failure.

AIMS: Observational studies in selected populations have suggested that microvolt T-wave alternans (MTWA) testing may identify patients with heart failure (HF) at risk of sudden cardiac death. The aims of this study were to investigate the utility of MTWA testing in an unselected population of patients with HF and to evaluate the clinical characteristics associated with the MTWA results. METHODS AND RESULTS: A total of 1003 patients hospitalized with decompensated HF were enrolled. MTWA testing was planned 1 month post-discharge; 648 patients returned for MTWA testing. Mean age was 70.8 ± 10.6 years and 58% were male. Of these patients who returned, 318 (49%) were ineligible for MTWA testing due to atrial fibrillation (AF), pacemaker dependency, or physical inability to undertake the test. Of the MTWA tests, 100 (30%) were positive, 78 (24%) were negative, and 152 (46%) were indeterminate; 112/152 indeterminate tests (74%) occurred because of failure to achieve target heart rate (HR) due to chronotropic incompetence or physical limitations. There were differences in patient characteristics according to MTWA result. Independent predictors of a negative result included younger age and higher left ventricular ejection fraction (LVEF). Independent predictors of a positive result included higher HR during MTWA testing and lower LVEF. Independent predictors of an indeterminate result included older age and history of previous/paroxysmal AF. CONCLUSIONS: Only half of patients with HF are eligible for MTWA testing and the most common result is an indeterminate test. Patients with positive and indeterminate tests have different clinical characteristics. MTWA treadmill testing is not widely applicable in typical HF patients and is unlikely to refine risk stratification for sudden death on a population level.

Aldosterone and cortisol predict medium-term left ventricular remodelling following myocardial infarction.

AIMS: Mineralocorticoid receptor (MR) antagonists improve cardiovascular outcomes in patients with heart failure complicating acute myocardial infarction (AMI) and in chronic heart failure. It is unclear whether these beneficial effects are due solely to aldosterone blockade, as MR has a similar affinity for cortisol. We examined the relationships between plasma and urinary steroid hormones and left ventricular (LV) remodelling in patients with LV dysfunction following AMI. METHODS AND RESULTS: Plasma concentrations of renin, aldosterone, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and 24 h urinary excretion rates of tetrahydroaldosterone (THAldo) and total cortisol metabolites were measured in 93 patients at a mean of 46 h following AMI prior to contrast-enhanced cardiac magnetic resonance (ceCMR). Patients were then randomized to 24 weeks of placebo or eplerenone therapy in addition to standard treatment, after which ceCMR was repeated. In placebo-treated patients, aldosterone, NT-proBNP, and excretion rates of THAldo and total cortisol metabolites were univariate predictors of remodelling (i.e. change in LV end-systolic volume index); aldosterone (P = 0.040) and total cortisol metabolite excretion (P = 0.038) remained independent predictors on multivariate analysis. None of the measured biomarkers predicted remodelling in the presence of eplerenone. Plasma and urinary aldosterone measures, and urinary cortisol metabolites, were not only related to larger infarct volumes and greater infarct remodelling over time, but were also higher in patients with microvascular obstruction on baseline ceCMR. CONCLUSION: Aldosterone and cortisol are associated with medium-term LV remodelling when measured early after AMI. The beneficial effects of MR antagonism may relate to blockade of both aldosterone- and cortisol-induced MR activation.