Predictive biomarkers for death and rehospitalization in comorbid frail elderly heart failure patients.

BACKGROUND: Heart failure (HF) is associated with a high rate of readmissions within 30 days post-discharge and in the following year, especially in frail elderly patients. Biomarker data are scarce in this high-risk population. This study assessed the value of early post-discharge circulating levels of ST2, NT-proBNP, CA125, and hs-TnI for predicting 30-day and 1-year outcomes in comorbid frail elderly patients with HF with mainly preserved ejection fraction (HFpEF). METHODS: Blood samples were obtained at the first visit shortly after discharge (4.9 ± 2 days). The primary endpoint was the composite of all-cause mortality or HF-related rehospitalization at 30 days and at 1 year. All-cause mortality alone at one year was also a major endpoint. HF-related rehospitalizations alone were secondary end-points. RESULTS: From February 2014 to November 2016, 522 consecutive patients attending the STOP-HF Clinic were included (57.1% women, age 82 ± 8.7 years, mean Barthel index 70 ± 25, mean Charlson comorbidity index 5.6 ± 2.2). The composite endpoint occurred in 8.6% patients at 30 days and in 38.5% at 1 year. In multivariable analysis, ST2 [hazard ratio (HR) 1.53; 95% CI 1.19-1.97; p = 0.001] was the only predictive biomarker at 30 days; at 1 year, both ST2 (HR 1.34; 95% CI 1.15-1.56; p < 0.001) and NT-proBNP (HR 1.19; 95% CI 1.02-1.40; p = 0.03) remained significant. The addition of ST2 and NT-proBNP into a clinical predictive model increased the AUC from 0.70 to 0.75 at 30 days (p = 0.02) and from 0.71 to 0.74 at 1 year (p < 0.05). For all-cause death at 1 year, ST2 (HR 1.50; 95% CI 1.26-1.80; p < 0.001), and CA125 (HR 1.41; 95% CI 1.21-1.63; p < 0.001) remained independent predictors in multivariable analysis. The addition of ST2 and CA125 into a clinical predictive model increased the AUC from 0.74 to 0.78 (p = 0.03). For HF-related hospitalizations, ST2 was the only predictive biomarker in multivariable analyses, both at 30 days and at 1 year. CONCLUSIONS: In a comorbid frail elderly population with HFpEF, ST2 outperformed NT-proBNP for predicting the risk of all-cause mortality or HF-related rehospitalization. ST2, a surrogate marker of inflammation and fibrosis, may be a better predictive marker in high-risk HFpEF.

Serum Neprilysin and Recurrent Admissions in Patients With Heart Failure.

BACKGROUND: Our aim was to evaluate the association between the soluble form of neprilysin (sNEP) levels and long-term all-cause, cardiovascular, and acute heart failure (AHF) recurrent admissions in an ambulatory cohort of patients with heart failure. sNEP has emerged as a new biomarker with promising implications for prognosis and therapy in patients with heart failure. Reducing the recurrent admission rate of heart failure patients has become an important target of public health planning strategies. METHODS AND RESULTS: We measured sNEP levels in 1021 consecutive ambulatory heart failure patients. End points were the number of all-cause, cardiovascular, and AHF hospitalizations during follow-up. We used covariate-adjusted incidence rate ratios to identify associations. At a median follow-up of 3.4 years (interquartile range: 1.8-5.7), 391 (38.3%) patients died, 477 (46.7%) patients had 1901 all-cause admissions, 324 (31.7%) patients had 770 cardiovascular admissions, and 218 (21.4%) patients had 488 AHF admissions. The medians for sNEP and amino-terminal pro-brain natriuretic peptide were 0.64 ng/mL (interquartile range: 0.39-1.22) and 1248 pg/mL (interquartile range: 538-2825), respectively. In a multivariate setting, the adjusted incidence rate ratios for the top (>1.22 ng/mL) versus the bottom (≤0.39 ng/mL) quartiles of sNEP were 1.37 (95% confidence interval: 1.03-1.82), P=0.032; 1.51 (95% confidence interval: 1.10-2.06), P=0.010; and 1.51 (95% confidence interval: 1.05-2.16), P=0.026 for all-cause, cardiovascular, and AHF admissions, respectively. CONCLUSIONS: Elevated sNEP levels predicted an increased risk of recurrent all-cause, cardiovascular, and AHF admissions in ambulatory patients with heart failure.

Bloodstream Amyloid-beta (1-40) Peptide, Cognition, and Outcomes in Heart Failure.

INTRODUCTION AND OBJECTIVES: In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aß40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF. METHODS: Bloodstream Aß40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death. RESULTS: Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aß40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aß40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P < .001). There were no differences in Aß40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aß40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P < .001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aß40 improved calibration and patient reclassification. CONCLUSIONS: Blood levels of Aß40 are not associated with cognitive decline in HF. Circulating Aß40 was predictive of mortality and may indicate systemic aging.

Association of the IGF1/pregnancy-associated plasma protein-A system and adipocytokine levels with the presence and the morphology of carotid plaques in type 2 diabetes mellitus patients with stable glycaemic control.

OBJECTIVE: Pregnancy-associated plasma protein-A (PAPP-A) has been implicated in the atherosclerotic process through regulation of local expression of IGF1. In type 2 diabetes mellitus, glycaemic control has been involved in PAPP-A expression. We compared PAPP-A, IGF1, inflammatory markers and adiponectin concentrations in type 2 diabetic patients with and without carotid plaques and evaluated the relationship between these serum parameters and ultrasound carotid markers of atherosclerosis. METHODS: We studied 125 consecutive type 2 diabetic patients. Clinical data, metabolic variables, hemostatic factors (plasma type-1 plasminogen activator inhibitor, fibrinogen), high-ultrasensitive C reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, adiponectin, IGF1 and PAPP-A were determined. Patients were classified into two groups according to the presence of carotid plaques on ultrasound. Carotid intima-media thickness (IMT) and morphology of carotid plaques were evaluated. RESULTS: The mean age was 61.5+/-7.3 years and the mean glycated hemoglobin of 6.8+/-0.9%. A total of 60% presented carotid plaques. Both groups were homogeneous in anthropometric data, biochemical determinations and hemostatic factors. Adiponectin, hsCRP, TNF-alpha and IL-6 were similar in both groups. No differences were observed in serum PAPP-A (0.46 (0.22-0.86) vs 0.38 (0.18-0.66) mIU/l and in SDS IGF1 (-0.34+/-1.38 vs -0.67+/-1.35)) in patients with and without carotid plaques respectively. PAPP-A and IGF1 were not correlated with IMT. CONCLUSIONS: Serum PAPP-A and IGF1 do not appear to be useful serum biomarkers for carotid atherosclerosis in type 2 diabetic patients with stable glycemic control, despite scientific evidence of their local role in atherosclerosis.

Homocysteine, C-reactive protein, lipid peroxidation and mortality in haemodialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is common in haemodialysis patients with chronic renal insufficiency and is the leading cause of death. The accelerated state of atherosclerosis found in these patients is due to a combination of different mechanisms. Recent studies confirm that inflammation plays an important role in the development of atherosclerosis. However, the role of hyperhomocysteinaemia and the immune response to oxidation of low-density lipoproteins (LDL) remains unclear and studies show contradictory results. The objective of this study was to determine whether there is a relationship between inflammation, hyperhomocysteinaemia and oxidative stress and whether these CVD risk factors are predictors of mortality in haemodialysis patients. METHODS: A prospective follow-up study was carried out in 94 stable, chronic haemodialysis patients for 24 months (July 1999-July 2001). All the patients were given folic acid and vitamin B complex supplements. Homocysteine was determined by fluorescence polarization immunoassay. C-reactive protein (CRP) levels were determined by chemiluminescent enzyme-labelled immunometric assay. Plasma copper oxidized anti-LDL (oxLDL) antibodies were measured by ELISA using native LDL and oxLDL as antigens. RESULTS: Thirty-two patients died during the study and 59.3% of the deaths could be attributed to CVD (eight to acute myocardial infarction and 11 to non-coronary vascular disease). The patients had slight hyperhomocysteinaemia (25.8 +/- 7.82 micromol/l), evidence of inflammation (CRP 5.16 mg/l (0.35-88.7)) and oxidative stress (oxLDL antibodies = 162 +/- 77 optical density at 495 nm x 1000). Age (P < 0.01), CRP (P = 0.03) and the oxLDL antibody titre (P < 0.01) were predictive of mortality. The patients who died from heart disease showed higher oxLDL antibody titres (P = 0.03). No correlation was found between homocysteine, CRP and the oxLDL antibody titre, or between serum homocysteine levels and the different causes of mortality. CONCLUSIONS: These results suggest that lipid peroxidation and inflammation, but not hyperhomocysteinaemia, are the main risk factors for mortality in haemodialysis patients receiving vitamin supplements. As the study was carried out in a relatively limited number of patients, our findings need to be confirmed in a larger patient population.