R. A. De Boer

The fibrosis marker galectin-3 and outcome in the general population

Abstract.  de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJL, van der Harst P (University of Groningen). The fibrosis marker galectin‐3 and outcome in the general population. J Intern Med 2012; 272: 55–64.

Telomere length loss due to smoking and metabolic traits

Human age‐dependent telomere attrition and telomere shortening are associated with several age‐associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length.

Vitamin D Biology in Heart Failure: Molecular Mechanisms and Systematic Review

Vitamin D has recently been suggested as an important mediator of blood pressure and cardiovascular disease, including heart failure. In patient with heart failure, low vitamin D levels are associated with adverse outcome and correlate with established clinical correlates and biomarkers. Many precursor states of heart failure, such as hypertension, atherosclerosis, and diabetes are more prevalent in subjects with low vitamin D levels. Recent experimental data have provided clues how vitamin D might exert cardioprotective effects. The steroid hormone vitamin D regulates gene expression of many genes that play a prominent role in the progression of heart failure, such as cytokines and hormones. Specifically, vitamin D is a negative regulator of the hormone renin, the pivotal hormone of the renin-angiotensin system. Mechanistic insights were gained by studying mice deficient for the vitamin D receptor, which develop hypertension and adverse cardiac remodeling mediated via the renin-angiotensin system. Furthermore, vitamin D receptor is expressed in the heart and regulated under pro-hypertrophic stimuli and vitamin D as receptor has been associated with the expression of other hypertrophic genes such as natriuretic peptides. So, epidemiological data and mechanistic studies have provided strong support for a potentially cardioprotective effect of vitamin D. It remains unclear if vitamin D supplementation is beneficial in preventing heart failure or if it could be a therapeutic addendum in the treatment of heart failure. This review summarizes current knowledge on vitamin D and its biology in heart failure.

The fibrosis-cell death axis in heart failure

Cardiac stress can induce morphological, structural and functional changes of the heart, referred to as cardiac remodeling. Myocardial infarction or sustained overload as a result of pathological causes such as hypertension or valve insufficiency may result in progressive remodeling and finally lead to heart failure (HF). Whereas pathological and physiological (exercise, pregnancy) overload both stimulate cardiomyocyte growth (hypertrophy), only pathological remodeling is characterized by increased deposition of extracellular matrix proteins, termed fibrosis, and loss of cardiomyocytes by necrosis, apoptosis and/or phagocytosis. HF is strongly associated with age, and cardiomyocyte loss and fibrosis are typical signs of the aging heart. Fibrosis results in stiffening of the heart, conductivity problems and reduced oxygen diffusion, and is associated with diminished ventricular function and arrhythmias. As a consequence, the workload of cardiomyocytes in the fibrotic heart is further augmented, whereas the physiological environment is becoming less favorable. This causes additional cardiomyocyte death and replacement of lost cardiomyocytes by fibrotic material, generating a vicious cycle of further decline of cardiac function. Breaking this fibrosis-cell death axis could halt further pathological and age-related cardiac regression and potentially reverse remodeling. In this review, we will describe the interaction between cardiac fibrosis, cardiomyocyte hypertrophy and cell death, and discuss potential strategies for tackling progressive cardiac remodeling and HF.

Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats.

Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)‐induced hypertensive cardiac disease in rats.

An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended‐release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1‐/4.6‐fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose–response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT‐HF‐defined titration schedule remains recommended for all patients, regardless of genotype.

Biomarkers in heart failure with preserved ejection fraction

Biomarkers are widely used and studied in heart failure. Most studies have described the utility and performance of biomarkers in sub-studies of randomised clinical trials, where the vast majority of the patients suffered from heart failure with reduced ejection fraction (HFrEF), and not with preserved ejection fraction (HFpEF). As a result, there is a scarcity of data describing the levels, dynamics, clinical and biochemical correlates, and biology of biomarkers in patients suffering from HFpEF, whereas HFpEF is in fact a very frequent clinical entity. This article discusses the value of different biomarkers in HFpEF. We describe various aspects of natriuretic peptide measurements in HFpEF patients, with a focus on diagnosis, prognosis and the risk prediction of developing heart failure. Further, we will discuss several emerging biomarkers such as galectin-3 and suppression of tumorigenicity 2, and recently discovered ones such as growth differentiation factor-15 and syndecan-1.

Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10−5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD. Genetic determinants of chronic mucus hypersecretion may differ by COPD status http://ow.ly/AeqCr

Recombinant Human Epo Treatment: Beneficial in Chronic Kidney Disease, Chronic Heart Failure, or Both? Editorial to: "Correction of Anemia with Erythropoietin in Chronic Kidney Disease (Stage 3 or 4): Effects on Cardiac Performance by Pappas et al."

For over two decades now, the recombinant form of erythropoietin (RhEPO) is used for the treatment of anemia in end-stage renal disease patients. Initial studies indicated an improvement in quality of life [1]. However, neutral/ negative data from two randomized controlled trials testing RhEPO to correct anemia in chronic kidney disease (CKD) were recently reported [2, 3]. The CHOIR study evaluated the effects of achieving high Hb levels (13.5 g/dl) compared to lower Hb levels (11.3 g/dl) on cardiovascular complications in CKD patients with an eGFR ≤50 ml/min/ 1.73 m. This study was prematurely halted, because of an increased adverse event rate in the high Hb group [2]. The CREATE study evaluated the effect of complete Hb correction (13.0 to 15.0 g/dl) to lower hemoglobin (Hb) correction (10.5–11.5 g/dl) in CKD patients with an eGFR <35 ml/min/1.73 m. In these patients complete correction of Hb did not change the risk on cardiovascular events [3]. So, both studies failed to demonstrate a better survival by correcting Hb levels to normal values, although both studies had an open-label design and were not placebocontrolled. Currently, a large, randomized, placebo-controlled, double blind trial to evaluate the effect of RhEPO treatment (to achieve Hb levels of 13.0 g/dl) on cardiovascular events in anemic CKD patients (TREAT) is ongoing [4]. A recent statement from the DSMB conveyed no evidence for terminating the TREAT study. Of note, this analysis was based on more endpoints than both CREATE and CHOIR together. In contrast to studies in CKD patients, two recent randomized, double-blind, placebo controlled studies with anemic chronic heart failure (CHF) patients consistently indicated beneficial cardiovascular and quality of life effects of RhEPO treatment [5, 6]. The first study by Ponikowski et al. [5] included 41 anemic CHF patients who were randomly assigned to either receive darbepoetin-alpha or placebo for 26 weeks to reach a target Hb of 13–15 g/dl. RhEPO increased Hb and in the treatment group, quality of life improved and a trend towards exercise duration was observed. In another study, van Veldhuisen et al. [6] evaluated the effect of weight-based and fixed starting dose RhEPO treatment compared to placebo in 165 anemic CHF patients. After 26 weeks, both RhEPO groups showed similar effects on Hb concentrations and this was associated with an improvement in quality of life. Importantly, both studies showed no difference in the incidence of adverse events. Thus, results from studies executed primarily in anemic CKD patients (neutral/negative) contrasted with results from studies executed primarily in anemic CHF patients (mainly positive). Notably, only 32% of the patients in CREATE and 24% in CHOIR had signs of heart failure. Alternatively, only the minority of anemic CHF patients had an eGFR <35–50 ml/min/1.73 m. So, there was little overlap between patient groups in these studies. Therefore, the study by Pappas et al. [7] in this present issue of Cardiovascular Drugs and Therapy is particularly interesting, because it brings both worlds together. They aimed to determine the effects of RhEPO (targeting at Hb ≥13.0 g/dl) on cardiac structure and function in patients with CKD. Although systolic left ventricular function was generally normal, diastolic dysfunction and left ventricular hypertrophy was already present in a large number of patients. They demonstrated that RhEPO treatment resulted Cardiovasc Drugs Ther (2008) 22:1–2 DOI 10.1007/s10557-008-6079-x

Recombinant human epo treatment: Beneficial in chronic kidney disease, chronic heart failure, or both?

For over two decades now, the recombinant form of erythropoietin (RhEPO) is used for the treatment of anemia in end-stage renal disease patients. Initial studies indicated an improvement in quality of life [1]. However, neutral/ negative data from two randomized controlled trials testing RhEPO to correct anemia in chronic kidney disease (CKD) were recently reported [2, 3]. The CHOIR study evaluated the effects of achieving high Hb levels (13.5 g/dl) compared to lower Hb levels (11.3 g/dl) on cardiovascular complications in CKD patients with an eGFR ≤50 ml/min/ 1.73 m. This study was prematurely halted, because of an increased adverse event rate in the high Hb group [2]. The CREATE study evaluated the effect of complete Hb correction (13.0 to 15.0 g/dl) to lower hemoglobin (Hb) correction (10.5–11.5 g/dl) in CKD patients with an eGFR <35 ml/min/1.73 m. In these patients complete correction of Hb did not change the risk on cardiovascular events [3]. So, both studies failed to demonstrate a better survival by correcting Hb levels to normal values, although both studies had an open-label design and were not placebocontrolled. Currently, a large, randomized, placebo-controlled, double blind trial to evaluate the effect of RhEPO treatment (to achieve Hb levels of 13.0 g/dl) on cardiovascular events in anemic CKD patients (TREAT) is ongoing [4]. A recent statement from the DSMB conveyed no evidence for terminating the TREAT study. Of note, this analysis was based on more endpoints than both CREATE and CHOIR together. In contrast to studies in CKD patients, two recent randomized, double-blind, placebo controlled studies with anemic chronic heart failure (CHF) patients consistently indicated beneficial cardiovascular and quality of life effects of RhEPO treatment [5, 6]. The first study by Ponikowski et al. [5] included 41 anemic CHF patients who were randomly assigned to either receive darbepoetin-alpha or placebo for 26 weeks to reach a target Hb of 13–15 g/dl. RhEPO increased Hb and in the treatment group, quality of life improved and a trend towards exercise duration was observed. In another study, van Veldhuisen et al. [6] evaluated the effect of weight-based and fixed starting dose RhEPO treatment compared to placebo in 165 anemic CHF patients. After 26 weeks, both RhEPO groups showed similar effects on Hb concentrations and this was associated with an improvement in quality of life. Importantly, both studies showed no difference in the incidence of adverse events. Thus, results from studies executed primarily in anemic CKD patients (neutral/negative) contrasted with results from studies executed primarily in anemic CHF patients (mainly positive). Notably, only 32% of the patients in CREATE and 24% in CHOIR had signs of heart failure. Alternatively, only the minority of anemic CHF patients had an eGFR <35–50 ml/min/1.73 m. So, there was little overlap between patient groups in these studies. Therefore, the study by Pappas et al. [7] in this present issue of Cardiovascular Drugs and Therapy is particularly interesting, because it brings both worlds together. They aimed to determine the effects of RhEPO (targeting at Hb ≥13.0 g/dl) on cardiac structure and function in patients with CKD. Although systolic left ventricular function was generally normal, diastolic dysfunction and left ventricular hypertrophy was already present in a large number of patients. They demonstrated that RhEPO treatment resulted Cardiovasc Drugs Ther (2008) 22:1–2 DOI 10.1007/s10557-008-6079-x