Genetically Determined High Levels of Iron Parameters Are Protective for Coronary Artery Disease

The observation that premenopausal women have a relatively low incidence of heart disease led in the nineteen eighties to the hypothesis that iron deficiency protects against heart diseases. These early observations were followed-up by conflicting epidemiological data. To confer causal relationships from epidemiological data is challenging as results can be influenced by residual confounding or reverse causation. For bias reduction, an alternative analysis strategy utilizing single-nucleotide polymorphisms (SNPs) as instrumental variables (Mendelian Randomization) has been developed. A recent study using 3 iron status associated SNPs suggested a protective effect of a higher iron status on the development of CAD.3 With a larger set of SNPs covering different components of iron metabolism, we aimed to provide a reliable answer to this lingering question

The influence of atrial fibrillation on the levels of NT-proBNP versus GDF-15 in patients with heart failure

In heart failure (HF), levels of NT-proBNP are influenced by the presence of concomitant atrial fibrillation (AF), making it difficult to distinguish between HF versus AF in patients with raised NT-proBNP. It is unknown whether levels of GDF-15 are also influenced by AF in patients with HF. In this study we compared the plasma levels of NT-proBNP versus GDF-15 in patients with HF in AF versus sinus rhythm (SR)

Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation and antiplatelet use

AIMS: Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort. METHODS AND RESULTS: We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation <20%. Univariable and multivariable logistic regression models were constructed to identify determinants for ID. We measured 92 cardiovascular markers (Olink Cardiovascular III) to establish a biomarker profile of ID. The primary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard deviation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (+interquartile range) were 4305 (2360-8329) ng/L. Iron deficiency was present in 1453 patients (61.6%), with highest prevalence in females (71.1% vs. 58.3%; P < 0.001). Independent determinants of ID were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein levels, lower serum albumin levels, and P2Y12 inhibitor use (all P < 0.05). None of these determinants were sex-specific. The biomarker profile of ID largely consisted of pro-inflammatory markers, including paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase type 5. In multivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of predictors of ID (hazard ratio 1.25, 95% confidence interval 1.06-1.46; P = 0.007). CONCLUSION: Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets)

Tumor biomarkers:association with heart failure outcomes

Background: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. Objectives: To explore the association between tumor biomarkers and HF outcomes. Methods: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumor biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1, and AFP. Results: During a median follow-up of 21 months, 555 (27%) patients reached the primary endpoint of all-cause mortality. CA125, CYFRA 21-1, CEA, and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P&lt;0.001, P for trend &lt;0.001), and were respectively associated with a hazard ratio of 1.17 (95% CI 1.12 – 1.23; P&lt;0.0001), 1.45 (95% CI 1.30 – 1.61; P&lt;0.0001), 1.19 (95% CI 1.09 – 1.30; P =0.006), and 1.10 (95% CI 1.05 – 1.16; P&lt;0.001)for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, hemoglobin, and beta-blocker). All tumor biomarkers (except AFP) had significant associations with secondary endpoints (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality, and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a non-inferior AUC compared to NT-proBNP (0.68) for all-cause mortality (P =0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC =0.71) improved the predictive value of the model for all-cause mortality (P =0.0002 compared to NT-proBNP). Conclusions: Several established tumor biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumor biomarkers are also dysregulated in HF

Hematinics in heart failure

Our research focused on iron deficiency in heart failure. Heart failure is a clinical syndrome which is characterized by a reduced pumping function of the heart. Many heart failure patients also have other diseases (comorbidity), of which iron deficiency is very common. Iron is an important part of the molecule hemoglobin, which is involved in oxygen transport in the human body. Moreover, iron has a role in the energy metabolism. Compared to heart failure patients without iron deficiency, patients with iron deficiency have more complaints, a reduced exercise tolerance and a worse prognosis. Treatment of iron deficiency with iron infusion leads to less complaint and less hospital admissions for heart failure. To date, little is known about the causes of iron deficiency in heart failure patients. My thesis focused on the causes of iron deficiency in heart failure patients. Our studies showed that iron deficiency can have multiple causes, for example the use of blood thinners or drugs that reduce the amount of acid that the stomach produces, reduced protein intake from the diet, symptoms of heart failure (breathlessness, swollen legs), inflammation and kidney failure. We also showed that there are several forms of iron deficiency, which should probably be treated differently. Each heart failure patient should be frequently screened for the presence of iron deficiency. Besides iron, vitamin B12 and folic acid are also important for the production of hemoglobin. Therefore, we also studied these vitamins. Compared to iron deficiency, vitamin B12 and folic acid deficiency are quite rare in heart failure patients

Comorbidities in Heart Failure

Comorbidities frequently accompany chronic heart failure (HF), contributing to increased morbidity and mortality, and an impaired quality of life. We describe the prevalence of several high-impact comorbidities in chronic HF patients and their impact on morbidity and mortality. Furthermore, we try to explain the underlying pathophysiological processes and the complex interaction between chronic HF and specific comorbidities. Although common risk factors are likely to contribute, it is reasonable to believe that factors associated with HF might cause other comorbidities and vice versa. Potential factors are inflammation, neurohormonal activation, and hemodynamic changes

Pharmacotherapy for co-morbidities in chronic heart failure:a focus on hematinic deficiencies, diabetes mellitus and hyperkalemia

INTRODUCTION: Chronic heart failure (HF) is frequently accompanied by one or more co-morbidities. The presence of co-morbidities in chronic HF is strongly correlated to HF severity and impaired outcome. AREAS COVERED: This review will address several co-morbidities with high prevalence and/or high impact in patients with chronic HF, including diabetes, anemia, hematinic deficiencies, and hyperkalemia. The background and subsequent pharmacotherapeutic options of these co-morbidities will be discussed. For this review, a MEDLINE search was performed. EXPERT OPINION: Heart failure is increasingly considered a multimorbid syndrome, including metabolic derangements and chronic inflammation. Persistent metabolic derangements and low-grade inflammation might lead to progression of HF and the development of co-morbidities. Although several co-morbidity-specific drugs became available in the past decade, most of these therapies are studied in relatively small cohorts using surrogate end-points. Therefore, larger studies are needed to address whether treating these co-morbidities will improve patient outcome in chronic HF