Molecular Medicine and Molecular Pathology for Haematologists:I. Gene Speak made Easy: An Overview of Genes and Gene Expression

Molecular Medicine and Molecular Pathology are integral parts of Haematology as we enter the new millennium. Their origins can be linked to fundamental developments in the basic sciences, particularly genetics, chemistry and biochemistry. The structure of DNA and the genetic code that it encrypts are the critical starting points to our understanding of these new disciplines. The genetic alphabet is a simple one, consisting of just 4 letters, buts its influence is crucial to human development and differentiation. The concept of a gene is not a new one but the Human Genome Project (a joint world-wide effort to characterise our entire genetic make-up) is providing an invaluable understanding of how genes function in normal cellular processes and pinpointing how disruption of these processes can lead to disease. Transcription and translation are the key events by which our genotype is converted to our phenotype (via a messenger RNA intermediate), producing the myriad proteins and enzymes which populate the cellular factory of our body. Unlike the bacterial or prokaryotic genome, the human genome contains a large amount of non coding DNA (less than 1% of our genome codes for proteins), and our genes are interrupted, with the coding regions or exons separated by non coding introns. Precise removal of the intronic material after transcription (though a process called splicing) is critical for efficient translation to occur. Incorrect splicing can lead to the generation of mutant proteins, which can have a dilaterious effect on the phenotype of the individual. Thus the 100,000-200,000 genes which are present in each cell in our body have a defined control mechanism permitting efficient and appropriate expression of proteins and enzymes and yet a single base change in just one of those genes can lead to diseases such as haemophilia or fanconis anaemia.

Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes

AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

Involvement of the atrial natriuretic peptide in cardiovascular pathophysiology and its relationship with exercise

In this minireview we describe the involvement of the atrial natriuretic peptide (ANP) in cardiovascular pathophysiology and exercise. The ANP has a broad homeostatic role and exerts complex effects on the cardio-circulatory hemodynamics, it is produced by the left atrium and has a key role in regulating sodium and water balance in mammals and humans. The dominant stimulus for its release is atrial wall tension, commonly caused by exercise. The ANP is involved in the process of lipolysis through a cGMP signaling pathway and, as a consequence, reducing blood pressure by decreasing the sensitivity of vascular smooth muscle to the action of vasoconstrictors and regulate fluid balance. The increase of this hormone is associated with better survival in patients with chronic heart failure (CHF). This minireview provides new evidence based on recent studies related to the beneficial effects of exercise in patients with cardiovascular disease, focusing on the ANP. © 2012 de Almeida et al; licensee BioMed Central Ltd.

Involvement of the atrial natriuretic peptide in cardiovascular pathophysiology and its relationship with exercise

In this minireview we describe the involvement of the atrial natriuretic peptide (ANP) in cardiovascular pathophysiology and exercise. The ANP has a broad homeostatic role and exerts complex effects on the cardio-circulatory hemodynamics, it is produced by the left atrium and has a key role in regulating sodium and water balance in mammals and humans. The dominant stimulus for its release is atrial wall tension, commonly caused by exercise. The ANP is involved in the process of lipolysis through a cGMP signaling pathway and, as a consequence, reducing blood pressure by decreasing the sensitivity of vascular smooth muscle to the action of vasoconstrictors and regulate fluid balance. The increase of this hormone is associated with better survival in patients with chronic heart failure (CHF). This minireview provides new evidence based on recent studies related to the beneficial effects of exercise in patients with cardiovascular disease, focusing on the ANP.

Controversies in cardiovascular medicine: Chronic stable coronary artery disease: drugs vs. revascularization

Coronary artery disease remains the leading cause of mortality in most industrialized countries, although age-standardized mortality related to coronary artery disease (CAD) has decreased by more than 40% during the last two decades. Coronary atherosclerosis may cause angina pectoris, myocardial infarction, heart failure, arrhythmia, and sudden death. Medical management of atherosclerosis and its manifestation aims at retardation of progression of plaque formation, prevention of plaque rupture, and subsequent events and treatment of symptoms, when these occur as well as treatment of the sequelae of the disease. Revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) is performed as treatment of flow-limiting coronary stenosis to reduce myocardial ischaemia. In high-risk patients with acute coronary syndromes (ACS), a routine invasive strategy with revascularization in most patients provides the best outcome with a significant reduction in death and myocardial infarction compared with an initial conservative strategy. Conversely, the benefit of revascularization among patients with chronic stable CAD has been called into question. This review will provide information that revascularization exerts favourable effects on symptoms, quality of life, exercise capacity, and survival, particularly in those with extensive CAD and documented moderate-to-severe ischaemia. Accordingly, CABG and PCI should be considered a valuable adjunct rather than an alternative to medical therapy.

Systems medicine and integrated care to combat chronic noncommunicable diseases

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.

[Effects of tobacco use on systemic health: relevant information for dentistry (II)--part 2: cardiovascular diseases and public health issues]

This is the sixth and concluding part of a series of publications from the Swiss task force named "Smoking - Intervention in the private dental office" on the topic "tobacco use and dental medicine". The focus of this review is the effects of smoking for the development of atherosclerosis as pathohistological correlate for acute coronary syndrome (ACS), arterial occlusive disease, and cerebrovascular diseases (stroke). Additionally, a causal relationship between tobacco use and an increased rate for complications during pregnancy and child birth will be discussed. Next to causal therapy of local and systemic diseases in general, an emphasis must be given to tobacco use prevention and cessation. Finally, important public health issues concerning smoking and tobacco use will be demonstrated, and options to improve the current situation will be presented.

Fluid intake and all-cause mortality, cardiovascular mortality, and kidney function: a population-based longitudinal cohort study

BACKGROUND Drinking eight glasses of fluid or water each day is widely believed to improve health, but evidence is sparse and conflicting. We aimed to investigate the association between fluid consumption and long-term mortality and kidney function. METHODS We conducted a longitudinal analysis within a prospective, population-based cohort study of 3858 men and women aged 49 years or older residing in Australia. Daily fluid intake from food and beverages not including water was measured using a food frequency questionnaire. We did multivariable adjusted Cox proportional hazard models for all-cause and cardiovascular mortality and a boot-strapping procedure for estimated glomerular filtration rate (eGFR). RESULTS Upper and lower quartiles of daily fluid intake corresponded to >3 L and <2 L, respectively. During a median follow-up of 13.1 years (total 43 093 years at risk), 1127 deaths (26.1 per 1000 years at risk) including 580 cardiovascular deaths (13.5 per 1000 years at risk) occurred. Daily fluid intake (per 250 mL increase) was not associated with all-cause [adjusted hazard ratio (HR) 0.99 (95% CI 0.98-1.01)] or cardiovascular mortality [HR 0.98 (95% CI 0.95-1.01)]. Overall, eGFR reduced by 2.2 mL/min per 1.73 m(2) (SD 10.9) in the 1207 (31%) participants who had repeat creatinine measurements and this was not associated with fluid intake [adjusted regression coefficient 0.06 mL/min/1.73 m(2) per 250 mL increase (95% CI -0.03 to 0.14)]. CONCLUSIONS Fluid intake from food and beverages excluding water is not associated with improved kidney function or reduced mortality.

Risk of Cardiovascular Events and Blood Pressure Control in Hypertensive HIV-Infected Patients: HIV Cohort Study (SHCS)

Background: Prevalence of hypertension in HIV infection is high, and information on blood pressure control in HIV-infected individuals is insufficient. We modeled blood pressure over time and the risk of cardiovascular events in hypertensive HIV-infected individuals. Methods: All patients from the Swiss HIV Cohort Study with confirmed hypertension (systolic or diastolic blood pressure above 139 or 89 mm Hg on 2 consecutive visits and presence of at least 1 additional cardiovascular risk factor) between April 1, 2000 and March 31, 2011 were included. Patients with previous cardiovascular events, already on antihypertensive drugs, and pregnant women were excluded. Change in blood pressure over time was modeled using linear mixed models with repeated measurement. Results: Hypertension was diagnosed in 2595 of 10,361 eligible patients. Of those, 869 initiated antihypertensive treatment. For patients treated for hypertension, we found a mean (95% confidence interval) decrease in systolic and diastolic blood pressure of −0.82 (−1.06 to −0.58) mm Hg and −0.89 (−1.05 to −0.73) mm Hg/yr, respectively. Factors associated with a decline in systolic blood pressure were baseline blood pressure, presence of chronic kidney disease, cardiovascular events, and the typical risk factors for cardiovascular disease. In patients with hypertension, increase in systolic blood pressure [(hazard ratio 1.18 (1.06 to 1.32) per 10 mm Hg increase], total cholesterol, smoking, age, and cumulative exposure to protease inhibitor–based and triple nucleoside regimens were associated with cardiovascular events. Conclusions: Insufficient control of hypertension was associated with increased risk of cardiovascular events indicating the need for improved management of hypertension in HIV-infected individuals.

High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis.

OBJECTIVES This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD). BACKGROUND Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. METHODS The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. RESULTS In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD. CONCLUSIONS High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.

The 10-year anniversary of the European Association for Cardiovascular Prevention and Rehabilitation: achievements and challenges

On the occasion of the 2014 European Society of Cardiology annual congress in Barcelona the European Association for Cardiovascular Prevention and Rehabilitation (EACPR) will celebrate its 10-year anniversary, having been initiated in Munich in 2004. In this article each EACPR president gives their personal recollections and views on the main achievements under their leadership and discusses the challenges for preventive cardiology that still lay ahead.

Psychosocial aspects in cardiac rehabilitation: From theory to practice. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology

A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with established CHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.

Sudden cardiac arrest in sports - need for uniform registration: A Position Paper from the Sport Cardiology Section of the European Association for Cardiovascular Prevention and Rehabilitation

There are large variations in the incidence, registration methods and reported causes of sudden cardiac arrest/sudden cardiac death (SCA/SCD) in competitive and recreational athletes. A crucial question is to which degree these variations are genuine or partly due to methodological incongruities. This paper discusses the uncertainties about available data and provides comprehensive suggestions for standard definitions and a guide for uniform registration parameters of SCA/SCD. The parameters include a definition of what constitutes an 'athlete', incidence calculations, enrolment of cases, the importance of gender, ethnicity and age of the athlete, as well as the type and level of sporting activity. A precise instruction for autopsy practice in the case of a SCD of athletes is given, including the role of molecular samples and evaluation of possible doping. Rational decisions about cardiac preparticipation screening and cardiac safety at sport facilities requires increased data quality concerning incidence, aetiology and management of SCA/SCD in sports. Uniform standard registration of SCA/SCD in athletes and leisure sportsmen would be a first step towards this goal.