Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy ...established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics‐based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine‐S‐methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA‐B44, HLA‐B*5701, CYP3A5, and factor V Leiden (FVL).
Clinical Pharmacology & Therapeutics (2011) 89 5, 662–673. doi:10.1038/clpt.2011.34
Emerging evidence supports that cancer incidence is increased in patients with cardiovascular (CV) disease and heart failure (HF), and patients with HF frequently die from cancer. Recently, data have ...been generated showing that circulating factors in relation to HF promote tumour growth and development in murine models, providing proof that a causal relationship exists between both diseases. Several common pathophysiological mechanisms linking HF to cancer exist, and include inflammation, neuro‐hormonal activation, oxidative stress and a dysfunctional immune system. These shared mechanisms, in combination with risk factors, in concert may explain why patients with HF are prone to develop cancer. Investigating the new insights linking HF with cancer is rapidly becoming an exciting new field of research, and we herein review the most recent data. Besides insights in mechanisms, we call for clinical awareness, that is essential to optimize treatment strategies of patients having developed cancer with a history of HF. Finally, ongoing and future trials should strive for comprehensive phenotyping of both CV and cancer end points, to allow optimal usefulness of data, and to better describe and understand common characteristics of these two lethal diseases.
Analysis of experiments aimed at understanding the genetic mechanisms of differentiation and growth of the heart, calls for detailed insights into cardiac growth and proliferation rate of myocytes ...and their precursors. Such insights in mouse heart development are currently lacking. We quantitatively assessed the 3D patterns of proliferation in the forming mouse heart and in the adjacent splanchnic mesoderm, from the onset of heart formation till the developed heart at late gestation. These results are presented in an interactive portable document format (Suppl. PDF) to facilitate communication and understanding. We show that the mouse splanchnic mesoderm is highly proliferative, and that the proliferation rate drops upon recruitment of cells into the cardiac lineage. Concomitantly, the proliferation rate locally increases at the sites of chamber formation, generating a regionalized proliferation pattern. Quantitative analysis shows a gradual decrease in proliferation rate of the ventricular walls with progression of development, and a base-to-top decline in proliferation rate in the trabecules. Our data offers clear insights into the growth and morphogenesis of the mouse heart and shows that in early development the phases of tube formation and chamber formation overlap. The resulting interactive quantitative 3D atlas of cardiac growth and morphogenesis provides a resource for interpretation of mechanistic studies.
► We present mouse heart development from first onset till late gestation. ► Interactive 3D reconstructions show heart morphology and proliferation patterns. ► Tube formation, tube elongation and early chamber formation overlap in time. ► Fast proliferation only occurs in splanchnic mesoderm and forming chambers. ► Proliferation rate is highest at the trabecular base and tapers off with distance.
Peripartum cardiomyopathy (PPCM) is a potentially life‐threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the ...months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre‐existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline‐directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress‐mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease‐specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter‐defibrillators, cardiac resynchronization therapy and implanted long‐term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.
Objectives
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.
Design and Methods
Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End‐stage Disease (PREVEND) study, an ongoing community‐based prospective cohort study initiated in 1997. Follow‐up data were available at two time‐points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics.
Results
We observed an average attrition rate of 0.47 ± 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39–60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist–hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001).
Conclusions
Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age‐associated diseases.
Recent studies have shown that the primary heart tube continues to grow by addition of cells from the coelomic wall. This growth occurs concomitantly with embryonic folding and formation of the ...coelomic cavity, making early heart formation morphologically complex. A scarcity of data on localized growth parameters further hampers the understanding of cardiac growth. Therefore, we investigated local proliferation during early heart formation. Firstly, we determined the cell cycle length of primary myocardium of the early heart tube to be 5.5 days, showing that this myocardium is nonproliferating and implying that initial heart formation occurs solely by addition of cells. In line with this, we show that the heart tube rapidly lengthens at its inflow by differentiation of recently divided precursor cells. To track the origin of these cells, we made quantitative 3D reconstructions of proliferation in the forming heart tube and the mesoderm of its flanking coelomic walls. These reconstructions show a single, albeit bilateral, center of rapid proliferation in the caudomedial pericardial back wall. This center expresses Islet1. Cell tracing showed that cells from this caudal growth center, besides feeding into the venous pole of the heart, also move cranially via the dorsal pericardial mesoderm and differentiate into myocardium at the arterial pole. Inhibition of caudal proliferation impairs the formation of both the atria and the right ventricle. These data show how a proliferating growth center in the caudal coelomic wall elongates the heart tube at both its venous and arterial pole, providing a morphological mechanism for early heart formation.
. 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.
Objective. Galectin‐3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin‐3 and cardiovascular (CV) risk factors and mortality in the general population.
Design and subjects. This study included 7968 subjects from the Prevention of REnal and Vascular ENd‐stage Disease (PREVEND) cohort, with a median follow‐up of approximately 10 years. Plasma galectin‐3 was measured in baseline samples.
Main outcome measures. We investigated the relationships between galectin‐3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all‐cause, CV and cancer mortality.
Results. The mean age of the population was 50 ± 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 ± 1.1 mmol L−1 and median galectin‐3 was 10.9 ng mL−1 interquartile range (IQR) 9.0–13.1. Galectin‐3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N‐terminal pro‐B‐type natriuretic peptide (P < 0.0001). We observed a strong association between galectin‐3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin‐3 levels (11.0 ng mL−1, IQR 9.1–13.4 vs. men (n = 3967) 10.7 ng mL−1, IQR 8.9–12.8; P < 0.0001), and galectin‐3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin‐3 levels independently predicted all‐cause mortality (hazard ratio per SD galectin‐3 1.09, 95% CI 1.01–1.19; P = 0.036), but not CV and cancer mortality separately.
Conclusions. Galectin‐3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin‐3 predicts all‐cause mortality in the general population.
Guillain–Barré syndrome (GBS) is a post-infectious disease in which the human peripheral nervous system is affected after infection by specific pathogenic bacteria, including
Campylobacter jejuni
. ...GBS is suggested to be provoked by molecular mimicry between sialylated lipooligosaccharide (LOS) structures on the cell envelope of these bacteria and ganglioside epitopes on the human peripheral nerves, resulting in autoimmune-driven nerve destruction. Earlier, the
C. jejuni
sialyltransferase (Cst-II) was found to be linked to GBS and demonstrated to be involved in the biosynthesis of the ganglioside-like LOS structures. Apart from a role in pathogenicity, we report here that Cst-II-generated ganglioside-like LOS structures confer efficient bacteriophage resistance in
C. jejuni
. By bioinformatic analysis, it is revealed that the presence of sialyltransferases in
C. jejuni
and other potential GBS-related pathogens correlated significantly with the apparent degeneration of an alternative anti-virus system: type II
C
lusters of
R
egularly
I
nterspaced
S
hort
P
alindromic
R
epeat and
as
sociated genes (CRISPR-Cas). Molecular analysis of the
C. jejuni
CRISPR-Cas system confirmed the bioinformatic investigation. CRISPR degeneration and mutations in the
cas
genes
cas2
,
cas1
and
csn1
were found to correlate with Cst-II sialyltransferase presence (
p
< 0.0001). Remarkably, type II CRISPR-Cas systems are mainly found in mammalian pathogens. To study the potential involvement of this system in pathogenicity, we inactivated the type II CRISPR-Cas marker gene
csn1
, which effectively reduced virulence in primarily
cst
-II-positive
C. jejuni
isolates. Our findings indicate a novel link between viral defence, virulence and GBS in a pathogenic bacterium.
Obesity is very common in patients with heart failure with preserved ejection fraction (HFpEF) and it has been suggested that obesity plays an important role in the pathophysiology of this disease. ...While body mass index defines the presence of obesity, this measure provides limited information on visceral adiposity, which is probably more relevant in the pathophysiology of HFpEF. Epicardial adipose tissue is the visceral fat situated directly adjacent to the heart and recent data demonstrate that accumulation of epicardial adipose tissue is associated with the onset, symptomatology and outcome of HFpEF. However, the mechanisms by which epicardial adipose tissue may be involved in HFpEF remain unclear. It is also questioned whether epicardial adipose tissue may be a specific target for therapy for this disease. In the present review, we describe the physiology of epicardial adipose tissue and the pathophysiological transformation of epicardial adipose tissue in response to chronic inflammatory diseases, and we postulate conceptual mechanisms on how epicardial adipose tissue may be involved in HFpEF pathophysiology. Lastly, we outline potential treatment strategies, knowledge gaps and directions for further research.