Association between early detected heart failure stages and future cardiovascular and non-cardiovascular events in the elderly (Copenhagen Heart Failure Risk Study).

BACKGROUND: Early stages of heart failure (HF) are associated with an increased risk of hospitalization and increased mortality, however the course of progression and the impact of non-cardiovascular comorbidities on adverse events in elderly high-risk patients are unknown. AIM: To examine the risk of future cardiovascular (CV) and non-CV events in early stages of HF in a cohort of elderly patients (age ≥ 60 with ≥ 1 risk factor for HF and without known or clinically suspected HF). METHODS: A total of 400 patients (American Heart Association HF stage A: N = 177; stage B: N = 150; stage C: N = 73) from the Copenhagen Heart Failure Risk Study were identified and followed for the main composite outcome of a HF hospitalization (HFH), ischemic heart disease (IHD), stroke, and all-cause death, recorded within the Danish nationwide registries. Non-CV hospitalization was a secondary outcome. Absolute risk was calculated by the Aalen-Johansen estimator. RESULTS: The median follow-up time was 3.3 years, total number of events were 83, and the 3-year risk (95% confidence interval) of the main outcome was 12.8% (7.8-17.9), 22.8% (16.1-29.6) and 31.8% (21.0-42.6) for patients with stage A, B, and C, respectively. 1.1% (0.0-2.7), 3.4% (1.0-6.3) and 10.0% (2.8-16.3) experienced HFH as their first event, whereas 37.3% (30.2-44.4), 49.7% (41.6-57.8) and 54.8% (43.4-66.2) were admitted for non-CV causes as their first event. CONCLUSION: The risk of HFH, IHD, stroke and all-cause death increased with severity of HF stage, and 10% of patients with undiagnosed HF stage C were admitted for HF within 3 years. However, the risk of non-CV hospitalizations was greater compared to the risk of experiencing HFH.

Early Stages of Obesity-related Heart Failure Are Associated with Natriuretic Peptide Deficiency and an Overall Lack of Neurohormonal Activation: The Copenhagen Heart Failure Risk Study.

Objective: This study evaluated the associations between the natriuretic peptide activity and the neurohormonal response in non-obese and obese outpatients with and without heart failure (HF). Background: Obesity-related HF may be a distinct subtype of HF. Obesity is associated with lower plasma concentrations of natriuretic peptides. The associations between obesity and neurohormonal activation estimated by mid-regional pro-adrenomedullin (MR-proADM) and copeptin in patients with HF is not elucidated. Methods: This prospective cohort-study included 392 outpatients ≥60years, plus ≥1 risk-factor(-s) for HF (hypertension, ischemic heart disease, atrial fibrillation, diabetes, chronic kidney disease), and without known HF. Patients were categorized 'non-obese' BMI = 18.5-29.9 kg/m2 (n = 273) and 'obese' BMI ≥ 30 kg/m2 (n = 119). The diagnosis of HF required signs, symptoms, and abnormal echocardiography. NT-proBNP, MR-proANP, MR-proADM, and copeptin were analyzed. Results: Obese patients were younger, had a higher prevalence of diabetes and chronic kidney disease, but a lower prevalence of atrial fibrillation. A total of 39 (14.3%) non-obese and 26 (21.8%) obese patients were diagnosed with HF. In obese patients, HF was not associated with higher plasma concentrations of NT-proBNP (Estimate: 0.063; 95%CI: -0.037-1.300; P = 0.064), MR-proANP (Estimate: 0.207; 95%CI: -0.101-0.515; P = 0.187), MR-proADM (Estimate: 0.112; 95%CI: -0.047-0.271; P = 0.168), or copeptin (Estimate: 0.093; 95%CI: -0.333-0.518; P = 0.669). Additionally, obese patients with HF had lower plasma concentrations of NT-proBNP (Estimate: -0.998; 95%CI: -1.778-0.218; P = 0.012), and MR-proANP (Estimate: -0.488; 95%CI: -0.845-0.132; P = 0.007) compared to non-obese patients with HF, whereas plasma concentrations of MR-proADM (Estimate: 0.066; 95%CI: -0.119-0.250; P = 0.484) and copeptin (Estimate: 0.140; 95%CI: -0.354-0.633; P = 0.578) were comparable. Conclusions: Patients with obesity-related HF have natriuretic peptide deficiency and lack of increased plasma concentrations of MR-proADM and copeptin suggesting that patients with obesity-related HF have a blunted overall neurohormonal activity.

Diagnostic utility of MR-proANP and NT-proBNP in elderly outpatients with a high risk of heart failure: the Copenhagen heart failure risk study.

Background: Amino-terminal-pro-B-type-natriuretic-peptide (NT-proBNP) is a diagnostic biomarker for heart failure (HF), but plasma concentrations are influenced by numerous factors. Mid-regional-pro-atrial-natriuretic-peptide (MR-proANP) have comparable diagnostic value in acute HF. However, data are lacking in the non-acute setting. This study sought to assess the diagnostic utility of MR-proANP in outpatients with a high risk of HF.Methods: This prospective study included 399 outpatients. Inclusion criteria were: age ≥ 60 years, ≥1 risk factor for HF (diabetes, chronic kidney disease, vascular disease, atrial fibrillation, hypertension), without known or suspected HF. Unrecognized HF was diagnosed based on clinical signs, patient-reported symptoms and echocardiography. Plasma concentrations of MR-proANP and NT-proBNP were analysed.Results: In total, 65 patients were diagnosed with HF or asymptomatic left ventricular systolic dysfunction (N = 12 LVEF ≤ 40%, N = 7 LVEF > 40% to ≤50%, N = 46 LVEF > 50%). Both MR-proANP (odds-ratio: 1.77; 95% CI:1.16-2.72; p = 0.009) and NT-proBNP (odds-ratio: 1.49; 95% CI:1.22-1.82; p < 0.001) were associated with HF. Area under receiver-operator characteristics curve (AUC) for the diagnosis of HF or asymptomatic left ventricular systolic dysfunction was higher for MR-proANP (AUC = 0.886; p < 0.001) and NT-proBNP (AUC = 0.910; p < 0.001) compared to patient-reported symptoms of HF (AUC = 0.830), but NT-proBNP added more diagnostic information compared to MR-proANP (p = 0.022).Conclusions: Both NT-proBNP and MR-proANP are useful biomarkers in the diagnosis of HF or asymptomatic left ventricular systolic dysfunction in a non-acute setting. However, NT-proBNP added more diagnostic information compared to MR-proANP.

Prevalence of early stages of heart failure in an elderly risk population: the Copenhagen Heart Failure Risk Study.

Aims: To describe the prevalence of heart failure (HF) stages in elderly outpatients with risk factors for HF but without known HF, and characterise the clinical, biochemical and echocardiographic findings in each stage. Background: Early stages of HF are underdiagnosed; nevertheless, they are associated with an increased risk of hospitalisation and increased mortality. The prevalence of HF stages in elderly high-risk patients is unknown. Methods: A total of 400 patients were consecutively included: ≥60 years old, ≥1 risk factor for HF (diabetes, chronic kidney disease, cardiovascular disease, atrial fibrillation, hypertension), and without known or suspected HF. HF stages were defined as the following: stage A (risk factor for HF, normal echocardiography), stage B (abnormal echocardiography, without symptoms of HF) and stage C (abnormal echocardiography, symptoms of HF, clinical signs/increased plasma aminoterminal pro-B-type natriuretic peptide [NT-proBNP] concentrations). Results: After thorough examination 44.25% of patients were categorised as HF stage A, 37.5% were HF stage B and 18.25% HF stage C. Those with higher stages of HF were older (p<0.001) and more often had atrial fibrillation (p=0.006). The median plasma NT-proBNP concentrations (pg/mL) were 132.5 for HF stage A, 275.5 for HF stage B and 400.0 for HF stage C (p<0.001). Detectable plasma troponin-I was more frequent with abnormal echocardiography: HF stage A 9.7%, HF stage B 27.3% and HF stage C 30.1% (p<0.001). HF stage C reported higher score on the Minnesota Living with Heart Failure Questionnaire (p<0.001). Conclusions: In an elderly high-risk population without known or suspected HF, more than half were HF stage B or C. Higher stages of HF had increased plasma concentrations of NT-proBNP and troponin-I, besides a reduced quality of life. Focus on symptoms and signs of HF in this population are warranted.

Influence of renal impairment on aldosterone status, calcium metabolism, and vasopressin activity in outpatients with systolic heart failure.

AIMS: Renal dysfunction (RD) is associated with increased morbidity and mortality in heart failure (HF). At present, no specific treatment for patients with RD, to prevent progression of HF, has been developed. How different hormone axes-and thereby potential treatment options-are affected by RD in HF warrants further investigations. METHODS AND RESULTS: Patients with left ventricular ejection fraction (LVEF) <0.45% were enrolled prospectively from an outpatient HF clinic. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR), and patients were grouped by eGFR: eGFR group I, ≥90 mL/min/1.73 m2 ; eGFR group II, 60-89 mL/min/1.73 m2 ; and eGFR group III, ≤59 mL/min/1.73 m2 . Multivariate linear regression models were developed to evaluate the associations between eGFR groups and hormones. A total of 149 patients participated in the study. Median age was 69 [interquartile range (IQR): 64-73] and 26% were female; LVEF was 33% (IQR: 27-39), 78% were in functional class II-III, median eGFR was 74 (54-89) mL/min/1.73 m2 , and median N-terminal pro-brain natriuretic peptide was 1303 pg/mL (IQR: 441-2740). RD was associated with increased aldosterone, parathyroid hormone (PTH), and copeptin concentrations (P < 0.05 for all) after adjustment for traditional confounders and medical treatment. CONCLUSIONS: RD is associated with increased concentrations of aldosterone, PTH, and copeptin in systolic HF outpatients. Our results underscore the importance of treatment with mineralocorticoid receptor antagonist in systolic HF in particular in patients with RD and suggest that vasopressin and parathyroid receptor antagonism are potential treatment options in HF patients with known RD.

Galectin 3: association to neurohumoral activity, echocardiographic parameters and renal function in outpatients with heart failure.

BACKGROUND: Galectin 3 (Gal-3) reflects cardiac fibrosis in heart failure HF, but has also been associated to renal fibrosis and impaired renal function. Previous research has suggested that Gal-3 could be a cardio-renal biomarker, but it has never been tested simultaneous in a single study whether Gal-3 reflects echocardiographic measures, neurohumoral activity and renal function. The aim of this study was to evaluate the relationship between plasma concentrations of Gal-3 and neurohumoral activity, myocardial and renal function in patients with HF, including advanced echocardiographic measures and 24-h urinary albumin excretion (albuminuria). METHODS: We prospectively enrolled 132 patients with reduced left ventricular ejection fraction (LVEF) referred to an outpatient HF clinic. The patients had a median age of 70 years (interquartile rage: 64-75), 26.5 % were female, median LVEF was 33 % (27-39 %) and 30 % were in NYHA class III-IV. RESULTS: Patients with plasma concentrations of Gal-3 above the median had significantly lower estimated glomerular filtration rate (eGFR) and this association remained significant in multivariate regression analysis (ß: -0.010; 95 % CI -0.012--0.008; P < 0.001), adjusted for age, gender, medical treatment. Plasma concentrations of Gal-3 were not associated with albuminuria (Beta: 0.008; 95 % CI:-0.028-0.045; P = 0.652). There were no association between plasma concentrations of Gal-3 and myocardial function or structure estimated by LVEF, LVmassIndex, LVIDd, E/é or LV global longitudinal strain (P > 0.05 for all). In multivariate analyses plasma concentrations of Gal-3 were significantly associated with the cardiac biomarkers: NT-proBNP (ß: 0.047; 95 % CI: 0.008-0.086; P = 0.020), proANP (ß: 0.137; 95 % CI: 0.067-0.207; P < 0.001), chromogranin A (ß: 0.123; 95 % CI: 0.052-0.194; P < 0.001) and Copeptin (ß: 0.080; 95 % CI: 0.000-0.160; P = 0.049). Multivariate analysis was adjusted for eGFR, age, gender and medical treatment. CONCLUSIONS: Increased plasma concentrations of Gal-3 are associated with reduced eGFR and increased plasma concentrations of NT-proBNP, proANP, chromogranin A and Copeptin, but not with echocardiographic parameters reflecting myocardial function. These results suggest that Gal-3 reflects both increased neurohumoral activity and reduced eGFR, but not myocardial function in patients with systolic HF.

Iron deficiency: Prevalence and relation to cardiovascular biomarkers in heart failure outpatients.

BACKGROUND: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. OBJECTIVES: To identify the prevalence of ID in a HF clinic and evaluate whether ID is associated with increased plasma concentrations of different cardiovascular biomarkers that carry a poor prognosis. METHODS: We prospectively included 149 patients with systolic HF referred to an outpatients HF clinic. ID was defined as ferritin<100 µg/L or ferritin 100-300 µg/L and Tranferin-saturation<0.20. Five different cardiovascular biomarkers were analyzed on frozen plasma. RESULTS: The patients had a median age of 70 (Interquartile range: 64-75) years, 25% were females, 29% were in functional class III-IV and LVEF was 32 (27-39) %. The prevalence of ID was 45% (95%-confidence interval (CI): 37-53%). In multivariate analyses, ID was not associated with plasma concentrations of troponin I, NT-proBNP, MR-proANP, chromogranin A or copeptin (P>0.05 for all) but with plasma concentrations of hs-CRP (odds ratio: 2.03, 95%-CI: 1.02-4.02, P=0.043). CONCLUSION: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF patients.

Alcohol intake and risk of venous thromboembolism. A Danish follow-up study.

Knowledge about the influence of alcohol intake on the risk of venous thromboembolism (VTE) is limited. We investigated the risk of VTE according to alcohol intake and drinking pattern among 27,178 men and 29,876 women participating in the Danish follow-up study Diet, Cancer and Health. Information on alcohol exposure and potential confounders were obtained from baseline questionnaires. We used Cox proportional hazard models to assess the association between VTE and alcohol intake. We performed separate analyses for the two sexes. During follow-up 619 incidents VTE events were verified. The lowest incidence rates of VTE were found for an average weekly intake of 3.9-13.9 standard drinks per weeks both for men and women. The adjusted hazard ratio (HR) was 0.91 [95%CI: 0.69-1.19] for women and 0.75 [95%CI: 0.56-1.02] for men according to an average alcohol intake of 3.9-13.9 standard drinks per week compared with low alcohol intake. In men, alcohol intake 2-6 times per week was associated with a lower risk of VTE compared to once per week (HR 0.77 [95%CI: 0.59-0.99]), but the difference disappeared after adjustment for total alcohol intake. We found no difference in the risk of VTE according to wine and beer intake. In conclusion, we found no consistent or statistically significant association between VTE and alcohol intake. Our data showed a u-formed association between alcohol intake and VTE, indicating that moderate alcohol intake may lower the risk of VTE with 10-30% in men.