Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF.

AIMS: We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia METHODS AND RESULTS: Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23-1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38-2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin. CONCLUSIONS: In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.

Vagus Nerve Stimulation Provides Multiyear Improvements in Autonomic Function and Cardiac Electrical Stability in the ANTHEM-HF Study.

BACKGROUND: Patients with heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased mortality risk. The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) trial reported improved heart rate variability (HRV) and heart rate turbulence (HRT) and reduced T-wave alternans (TWA) after 12 months of vagus nerve stimulation (VNS). We investigated whether the benefits of chronic VNS persist in the long term. METHODS AND RESULTS: Effects of chronic VNS on heart rate, HRV, HRT, TWA, R-wave and T-wave heterogeneity (RWH, TWH), and nonsustained ventricular tachycardia (NSVT) incidence were evaluated in all ANTHEM-HF patients with ambulatory ECG data at 24 and 36 months (n = 25). Autonomic markers improved significantly at 24 and 36 months compared to baseline [heart rate, square root of the mean squared differences of successive normal-to-normal intervals (rMSSD), standard deviation of the normal-to-normal intervals (SDNN), HF-HRV, HRT slope, P < 0.05]. Peak TWA levels remained reduced at 24 and 36 months (P < 0.0001). Reductions in RWH and TWH at 6 and 12 months persisted at 24 and 36 months (P < 0.01). NSVT decreased at 12, 24, and 36 months (P < 0.025). No sudden cardiac deaths, ventricular fibrillation, or sustained ventricular tachycardia occurred. CONCLUSION: In symptomatic patients with HFrEF, chronic VNS appears to confer wide-ranging, persistent improvements in autonomic tone (HRV), baroreceptor sensitivity (HRT), and cardiac electrical stability (TWA, RWH, TWH).

Pro-gastrin-releasing peptide and outcome in patients with heart failure and anaemia: results from the RED-HF study.

AIMS: Neuroendocrine activation is associated with poor outcome in heart failure (HF). The neuropeptide gastrin-releasing peptide (GRP), derived from the precursor proGRP1-125 (proGRP), has recently been implicated in inflammation and wound repair. We investigated the predictive value of proGRP on clinical outcomes in HF patients with reduced ejection fraction. METHODS AND RESULTS: The association between plasma proGRP (time-resolved immunofluorometric assay) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anaemia, enrolled in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial. Median proGRP levels in the RED-HF cohort were markedly increased [95 ng/L (25th, 75th percentile, 69-129 ng/L)] with 64% patients above the 80 ng/L reference limit. Baseline proGRP correlated with estimated glomerular filtration rate (r = 0.52), N terminal pro brain natriuretic peptide (r = 0.33), troponin T (r = 0.34), and haemoglobin (r = 0.16) (all P < 0.001). The incidence outcome increased with increasing tertiles of baseline proGRP (primary endpoint third tertile vs. the lowest tertile; hazard ratio 1.91; 95% confidence interval 1.60-2.28, P < 0.001). However, these associations were markedly attenuated and non-significant in adjusted models. No interaction between baseline proGRP and the effect of darbepoetin alfa treatment was detected. Moreover, no significant association between changes in proGRP during 6 month follow-up and outcome was observed. CONCLUSIONS: Pro-gastrin-releasing peptide is increased in patients with HF with reduced ejection fraction and anaemia, in particular in patients with poor renal function. However, proGRP adds little as a prognostic marker on top of conventional HF risk factors.

Cognitive function and anticoagulation control in patients with atrial fibrillation.

BACKGROUND: Patients with atrial fibrillation usually are elderly and may have cognitive dysfunction. These patients may receive less effective oral anticoagulation, resulting in more vascular events and bleeding. METHODS AND RESULTS: In an analysis of cognitive function associated with the time in therapeutic range (TTR) in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events, 2510 patients (mean age, 71+/-9.5 years) from 27 countries completed the Mini-Mental State Examination (MMSE). Of these patients, 171 (6.8%) had an MMSE score <24, suggesting dementia, and 194 (7.7%) had intermediate scores of 24 to 25. Low MMSE scores were correlated with a low TTR. Even mild cognitive impairment was associated with a TTR below the median (<65%). Patients with an MMSE score <26 had more vascular events (6.7% versus 3.6% per 100 patient-years; P=0.002) and more bleeding (9.6% versus 7% per 100 patient-years; P=0.04). After controlling for TTR, the MMSE no longer conferred increased risk, suggesting that if improved anticoagulation was provided, vascular events and bleeding would be reduced. Other independent factors associated with a TTR <65% were region of the world, recent initiation of vitamin K antagonist, type of anticoagulant, and concurrent use of amiodarone or insulin. After adjustment for these factors, lower MMSE scores still predicted a reduced TTR. CONCLUSIONS: Cognitive dysfunction is common in elderly patients with atrial fibrillation and is related to less effective anticoagulation and more vascular events. The MMSE identifies patients with atrial fibrillation in whom extra efforts are needed to maintain effective anticoagulation and improve outcomes. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243178.