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Microarray, SAGE and their applications to cardiovascular diseases.

The wealth of DNA data generated by the human genome project coupling with recently invented high-throughput gene expression profiling techniques has dramatically sped up the process for biomedical researchers on elucidating the role of genes in human diseases. One powerful method to reveal insight into gene functions is the systematic analysis of gene expression. Two popular high-throughput gene expression technologies, microarray and Serial Analysis of Gene Expression (SAGE) are capable of producing large amounts of gene expression data with the potential of providing novel insights into fundamental disease processes, especially complex syndromes such as cardiovascular disease, whose etiologies are due to multiple genetic factors and their interplay with the environment. Microarray and SAGE have already been used to examine gene expression patterns of cell-culture, animal and human tissues models of cardiovascular diseases. In this review, we will first give a brief introduction of microarray and SAGE technologies and point out their limitations. We will then discuss the major discoveries and the new biological insights that have emerged from their applications to cardiovascular diseases. Finally we will touch upon potential challenges and future developments in this area.

Cardiovascular Diseases↗

School children have leading risk factors for cardiovascular disease and diabetes: the Wausau SCHOOL project.

INTRODUCTION: Risk factors for cardiovascular disease and diabetes acquired in childhood commonly persist in later life and are particularly strong predictors of subclinical atherosclerosis in young adults. A rising tide of obesity and other lifestyle-related risk factors threatens to negate much of the success achieved in the prevention and treatment of these diseases. The SCHOOL project (School Children Have Leading Risk Factors for Cardiovascular Disease and Diabetes), was designed to measure the prevalence and magnitude of known risk factors in school-age children in Wausau, Wis. METHODS: Demographic data, anthropomorphic measures, family health history, diet and activity indices, and numerous laboratory measures were collected from a representative sample of students in grades 2, 5, 8, and 11. RESULTS: Clinically important disturbances of lipid metabolism were very common, even in the youngest participants. Of the children studied, 39% had at least 1 lipid abnormality and 22% had 2 or more. Abnormal blood pressure, overweight, and cigarette smoking were present in 29%, 16%, and 11% respectively. While elevated fasting glucose levels were uncommon, insulin resistance was noted in 25% of the sampled population and nearly 50% of sampled children with a body mass index greater than the 85th percentile in this survey. The number of children with multiple risk factors rose dramatically with age. By 11th grade, 38% of those surveyed had 2 or more risk factors and 23% had 3 or more. CONCLUSIONS: Using conservative definitions, significant abnormalities of lipid metabolism and other risk factors for cardiovascular disease and diabetes were common in our children. Risk profiles in older adolescents were worse than in the younger students and similar to what would be expected for adults with known coronary heart disease. In our community there is a growing consensus that we must take advantage of the multiple opportunities that exist to favorably alter the lifestyle patterns that put our children at risk.

Adolescent↗

Cigarette smoking and cardiovascular diseases.

That cigarette smoking is causally associated with development of cardiovascular disease is recognized unequivocally. Epidemiological studies worldwide have documented the many pathways of influence and synergism by which this ubiquitous but artificial habit exerts its ill effects on cardiorespiratory and other body systems, leading not only to cardiovascular disease but to cancer and other ailments. Current investigations among college alumni, women, elderly, and other subgroups provide data on how various independent influences combine with smoking to establish risk and promote pathogenesis of cardiovascular disease. Their findings also confirm that cigarette smoking is one of the strongest instigators. All of this knowledge has implications for the design and implementation of effective intervention programmes.

Age Factors↗

Racial and ethnic diversity in obesity and other risk factors for cardiovascular disease: implications for studies and treatment.

This review summarizes current knowledge about differences in cardiovascular disease and its risk factors among minorities in the US population. The limited information available about differences in the association of obesity with cardiovascular disease risk factors in minorities is described. Our thesis is that environment and its evolutionary influence are important in risk-factor changes, although genetic characteristics moderate the impact of these factors. This review attempts to illustrate how studies of minority groups can help us to understand the importance and interaction of factors leading to increased cardiovascular disease risk. We suggest guidelines for the design of studies that will help us to better explain differences in cardiovascular disease and its risk factors among minorities and to improve therapy for this common disorder. Because diabetes is a major topic of the First International Conference on Race, Ethnicity, and Health, data on this disease are used in many of the examples presented.

Cardiovascular Diseases↗

Use of plant stanol ester margarine among persons with and without cardiovascular disease: early phases of the adoption of a functional food in Finland.

BACKGROUND: The plant stanol ester margarine Benecol is a functional food that has been shown to lower effectively serum total and LDL-cholesterol. The purpose of this post-marketing study is to characterize users of plant stanol ester margarine with and without cardiovascular disease. METHODS: A cohort of plant stanol ester margarine users was established based on a compilation of 15 surveys conducted by the National Public Health Institute in Finland between 1996-2000. There were 29,772 subjects aged 35-84 years in the cohort. The users of plant stanol ester margarine were identified by the type of bread spread used. RESULTS: The plant stanol ester margarine was used as bread spread by 1332 (4.5%) subjects. Almost half (46%) of the users reported a history of cardiovascular disease. Persons with cardiovascular disease were more likely to use plant stanol ester margarine (8%) than persons without cardiovascular disease (3%). Users with and without cardiovascular disease seemed to share similar characteristics. In particular, they were elderly people with otherwise healthy life-styles and diet. They were less likely smokers, more likely physically active and less likely obese than nonusers. The users reported being in good or average health in general and having used cholesterol-lowering drugs. CONCLUSION: Plant stanol ester margarine seems to be used by persons for whom it was designed and in a way it was meant: as part of efforts for cardiovascular disease risk reduction.

Adult↗

Early growth and death from cardiovascular disease in women.

OBJECTIVE: To determine whether the link suggested between growth in utero and during infancy and death from cardiovascular disease in men is also present in women. DESIGN: Follow up study of women and men whose birth weight and weight at 1 year of age had been recorded. SETTING: Hertfordshire, England. SUBJECTS: 5585 women and 10,141 men born during 1911-30. MAIN OUTCOME MEASURES: Standardised mortality ratios for cardiovascular disease. RESULTS: Among women and men death rates from cardiovascular disease fell progressively between the low and high birth weights groups (chi 2 = 4.3, p = 0.04 for women, chi 2 = 8.5, p < 0.005 for men). Cardiovascular deaths in men but not women were also strongly related to weight at 1 year, falling progressively between the low and high weight groups (chi 2 = 27.5, p < 0.0001). The highest cardiovascular death rates in women were among those with below average birth weight but above average weight at 1 year. In men the highest rates were among those with below average birth weight and below average weight at 1 year. CONCLUSION: Relations between cardiovascular disease and birth weight are similar in men and women. In men cardiovascular disease is also related to weight gain in infancy.

Aged↗

Carotid artery wall morphology, haemostatic factors and cardiovascular disease. An ultrasound study in men at high and low risk for atherosclerotic disease.

The aim of this study was to examine whether there was a relationship between haemostatic factors and ultrasound-assessed morphology of the common carotid artery and cardiovascular disease in 57- to 77-year-old men at high risk for atherosclerotic disease (hypertension and at least one of the following risk factors: hypercholesterolaemia, smoking, diabetes mellitus). They were divided into one group with (n = 59) and one group without (n = 70) manifest cardiovascular disease. An age-matched reference group with no cardiovascular risk factors was used as a comparison (n = 51). Significant associations, independent of smoking, were found between plasma fibrinogen and both the maximal intima-media thickness and the occurrence of plaque in the high-risk group. High-risk patients with clinical signs of cardiovascular disease had higher levels of plasma fibrinogen and prothrombin 1 + 2 fragment compared with both high-risk patients without concomitant cardiovascular disease and low-risk subjects. Plasminogen activator inhibitor, von Willebrand factor and thrombin/antithrombin complex were increased in the high-risk group with signs of cardiovascular disease in comparison with the low-risk group. In conclusion the results indicate that plasma fibrinogen may be operative in the development of atherosclerosis. Clinical signs of cardiovascular disease were associated with increased plasma levels of fibrinogen, von Willebrand factor, plasminogen activator inhibitor, thrombin/antithrombin complex and prothrombin 1 + 2 fragment.

Aged↗

Estimating the high risk group for cardiovascular disease in the Norwegian HUNT 2 population according to the 2003 European guidelines: modelling study.

OBJECTIVE: To estimate the high risk group for cardiovascular disease in a well defined Norwegian population according to European guidelines and the systematic coronary risk evaluation system. DESIGN: Modelling study. SETTING: Nord-Tröndelag health study 1995-7 (HUNT 2), Norway. PARTICIPANTS: 5548 participants of the Nord-Tröndelag health study 1995-7, aged 40, 50, 55, 60, and 65. MAIN OUTCOME MEASURES: Distribution of risk categories for cardiovascular disease, with emphasis on the high risk group. MAIN RESULTS: At age 40, 22.5% (95% confidence interval 19.3% to 25.7%) of women and 85.9% (83.2% to 88.6%) of men were at high risk of cardiovascular disease. Corresponding numbers at age 50 were 39.5% (35.9% to 43.1%) and 88.7% (86.3% to 91.0%) and at age 65 were 84.0% (80.6% to 87.4%) and 91.6% (88.6% to 94.1%). At age 40, one out of 10 women and no men would be classified at low risk for cardiovascular disease. CONCLUSION: Implementation of the 2003 European guidelines on prevention of cardiovascular disease in clinical practice would classify most adult Norwegians at high risk for fatal cardiovascular disease.

Adult↗

[Correlation between body mass index, lipoprotein (a) level and positive family history of cardiovascular diseases in children and adolescents with obesity, hypertension and diabetes].

The study was carried out in a group of 285 children and adolescents aged 4-20 yrs. Children were divided according to their main disease: group with obesity, obesity and coexisting hypertension, hypertension and diabetes. Each group was divided into children with positive or negative family history of cardiovascular diseases. We assessed routine lipid parameters, body mass index and new atherosclerosis risk factors: lipoprotein (a), apolipoproteins A-I and B, homocysteine, fibrinogen, t-PA and PAI-1. Positive family history of cardiovascular diseases was found in 28% families, and in 8% families it was premature cardiovascular disease. In 48% children we found hypertension in family. Children with positive family history had significantly higher body mass index (25.4 vs 23.8 kg/m2). In the group with obesity and hypertension we found significantly higher cholesterol (182 vs 160 mg/dl) and LDL-cholesterol level (114 vs 93 mg/dl). Lipoprotein(a) level was significantly higher in children with positive family history (38 vs 28 mg/dl). Significant differencies were also found in apolipoprotein B level (90 vs 84 mg/dl). In logistic regression analysis only BMI and lipoprotein(a) were significant in predicting future cardiovascular events in children. Obese, hypertensive and diabetic children often come from families with cardiovascular diseases. Hypertension is the most often prevalent atherosclerosis risk factor in families. Children with positive family history of cardiovascular diseases have significantly higher body mass index. Out of new atherosclerosis risk factors lipoprotein(a) and apolipoprotein B may have real value in predicting future cardiovascular disease in the child. The aim of the study was to compare obese, hypertensive and diabetic children with positive and negative family history of cardiovascular diseases. In the work we have tried to find which of the new atherosclerosis risk factors may have the real value in predicting future cardiovascular events in children already predisposed to atherosclerosis.

Adolescent↗

Resource implications and health benefits of primary prevention strategies for cardiovascular disease in people aged 30 to 74: mathematical modelling study.

OBJECTIVE: To develop a model to determine resource costs and health benefits of implementing guidelines for the prevention of cardiovascular disease in primary care. DESIGN: Modelling of data from six strategies for prevention of cardiovascular disease. Strategies incorporated two ways of identifying patients for assessment: traditional (assessment of all adults) and novel (preselection of patients for assessment using a prior estimate of their risk of cardiovascular disease). Three treatment strategies were modelled in conjunction with each identification strategy. SETTING: England. SUBJECTS: Patients aged 30 to 74 eligible for primary prevention strategies for cardiovascular disease who were selected from a hypothetical population of 2000. MAIN OUTCOME MEASURES: Resource costs of assessing eligible adults, providing treatment and follow up to those eligible, and number of cardiovascular events this should prevent. RESULTS: Novel strategies prevented more cardiovascular disease, at lower cost, than traditional strategies. Some treatment strategies prevent more cardiovascular disease with fewer resources than others. The findings were robust across a range of different assumptions about workload. CONCLUSION: Preselecting patients for assessment makes better use of staff time than assessing all adults. Treating many patients with low cost drugs is more efficient than prescribing a few patients intensive antihypertensives and statins. Authors of guidelines should model workload implications and health benefits of following their recommendations.

Adult↗

Cardiovascular disease: genes and public health.

INTRODUCTION: The advances in molecular biology hold great promise for complex conditions such as cardiovascular disease. Early accurate diagnosis and new preventive and treatment strategies are among the potential benefits of genetic understanding. Many genes and mutations have been discovered that contribute to rare Mendelian forms of cardiovascular disease. However, there has been little tangible success in defining specific mutations that explain the more common forms of cardiovascular disease. Of the numerous genes tested, inconsistent results are a recurring theme. METHODS: This review addresses broader issues that touch on the clinical and epidemiological context in which the genetics of cardiovascular disease might develop. How do genes and environment interact in cardiovascular disease? What characteristics of a marker might make it useful? How will genetic understanding be used? What is the place of physiology in molecular biology? Is the future of genetics in patient management or public health? RESULTS: It is concluded that individuals and communities are unlikely to accept widespread DNA screening, and less likely to tolerate genetic manipulation. Genetic complexity will make the identification of specific mutations an expensive and potentially thankless task. CONCLUSIONS: Genetics may reveal new pathophysiological mechanisms against which simple, safe and effective public health measures can bring benefit to the greatest number.

Cardiovascular Diseases↗

Efficacy of antihypertensive drug treatment according to age, sex, blood pressure, and previous cardiovascular disease in patients over the age of 60.

Results of the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial have been analysed in relation to age, sex, blood pressure, and previous cardiovascular disease. Cardiovascular mortality and the cardiovascular study-terminating events were significantly and independently related to treatment, age, cardiovascular complications at randomisation, and systolic but not diastolic blood pressure. The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry. There was some evidence that treatment effect decreases with advancing age. Little or no benefit from treatment could be demonstrated in patients over the age of 80 years, the great majority of whom were women.

Age Factors↗

Renal disease, the metabolic syndrome, and cardiovascular disease.

OBJECTIVES: To describe the association between renal disease and other features of the metabolic syndrome and its derivative illnesses among Australian Aborigines in remote settings. METHODS: Volunteering adults (N = 2019) in four remote communities were screened for risk factors and markers of renal disease, hypertension, and diabetes, and their cross-sectional associations were evaluated. Rates of the metabolic syndrome were estimated in one community with comprehensive screening data. The associations of albuminuria with hospitalizations, coronary heart events, and non-renal deaths were then followed for > 7 years in that same community. RESULTS: Rates of renal disease, hypertension, and diabetes all increased dramatically with age. They all overlapped. Renal disease and hypertension were the most prominent and earliest features of the syndrome, while diabetes was a later, less common and more variable manifestation. All were strongly correlated with waist measurements, and high waist measurements more comprehensively characterized those with illnesses than did the more restrictive definitions of the metabolic syndrome. Albuminuria predicted non-renal hospitalizations, first time coronary heart disease events, and all-cause death. CONCLUSION: Albuminuria/proteinuria is an early and dominant element of a symptom complex that is marked by higher waist measurements, and it strongly predicts all-cause and cardiovascular illnesses and deaths. This finding implies a common background of risk factors for renal disease, hypertension, diabetes, and cardiovascular risk. The findings support integrated, rather than disease-specific, surveillance programs, an important role for albuminuria in predicting non-renal risk, and a unified approach for primary and secondary prevention of all elements of the syndrome.

Adult↗

Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976.

OBJECTIVE: To examine the association between birth weight and non-fatal adult cardiovascular disease while controlling for potential confounders such as socioeconomic group and adult lifestyle. DESIGN: Retrospective self report of birth weight in an ongoing longitudinal cohort of nurses followed up by postal questionnaire every two years. SETTING: Nurses' health study, a cohort of 121700 women followed up since 1976. MAIN OUTCOME MEASURES: Non-fatal cardiovascular disease, including myocardial infarction, coronary revascularisation, and stroke. RESULTS: Among the 70297 women free of cardiovascular disease at baseline who reported birth weight in the 1992 questionnaire there were 1309 first cases of non-fatal cardiovascular disease. Increasing birth weight was associated with decreasing risk of non-fatal cardiovascular disease. There were 1216 first cases of non-fatal cardiovascular disease among women who were singletons and had been born full term; their relative risks adjusted for several cardiovascular risk factors were 1.49 (95% confidence interval 1.05 to 2.10) for birth weight < 2268 g (< 5 lb 0 oz); 1.25 (0.98 to 1.61) for birth weight 2268-2495 g (5 lb 0 oz to 5 lb 8 oz); 1.12 (0.98 to 1.27) for birth weight > 2495-3175 g (> 5 lb 8 oz to 7 lb 0 oz); 1.00 (referent) for birth weight > 3175-3856 g (> 7 lb 0 oz to 8 lb 8 oz); 0.96 (0.80 to 1.15) for birth weight > 3856-4536 g (> 8 lb 8 oz to 10 lb 0 oz); and 0.68 (0.46 to 1.00) for birth weight > 4536 g (> 10 lb 0 oz) (P value for trend = 0.0004). The inverse trend was apparent for both coronary heart disease and stroke. CONCLUSIONS: These data provide strong evidence of an association between birth weight and adult coronary heart disease and stroke.

Adult↗

Social support, marital status and living arrangement correlates of cardiovascular disease risk factors in the elderly.

Marital status and indices of social support are associated with mortality due to coronary heart disease and stroke. This association seems not entirely due to differences in recognised cardiovascular disease risk factors. The Western Sydney Stroke risk in the Elderly Study examined the relationship between marital status, living arrangements, widowhood and extent of social support, and risk factors for cardiovascular disease in men and women aged over 65 years. Unmarried men had the lowest mean HDL-C levels. Men living alone had the highest mean systolic blood pressures. The lower mean HDL-C levels and higher DBP levels seen among widows were not statistically significant after adjustment for differences in past medical history and education levels. The extent of social support was not associated with any significant differences in cardiovascular risk factor levels among men or women. We conclude that some of the increased risk of cardiovascular disease associated with socio-demographic factors among men in this age-group may be due to differences in primary cardiovascular disease risk factors. However, some of the mechanisms underlying risk of cardiovascular disease in this age-group remains obscure.

Activities of Daily Living↗

[The relationship between genetic polymorphisms and disease, illustrated by the renin-angiotensin-aldosterone system and cardiovascular disease].

The role of molecular genetics in the pathophysiology of various diseases is becoming clearer and clearer. In the field of cardiovascular diseases, molecular genetic aspects have been shown to play a definite role in the aetiology of these diseases. Several molecular-genetic variations called polymorphisms, occur in the population. The genes encoding the different components of the reninangiotensin-aldosterone system (RAAS), an important system in the regulation of the function and structure of the heart and vascular wall, also display polymorphisms. For some of these polymorphisms associations with various cardiovascular and renal diseases have been described. At present, this is particularly clear for the relation between angiotensin-converting-enzyme (ACE) polymorphism and the incidence of atherosclerotic complications and diabetic nephropathy, and for the relation between so-called M235 T-variant of the angiotensinogen gene and hypertension. Future research will have to show where it is worthwhile to use these and other polymorphisms as a marker for genetic risk. In what way the different RAAS-polymorphisms relate to functional abnormalities is as yet unclear, as are the potential therapeutic implications.

Angiotensin II↗

Differential management of cardiovascular disease in ESRD by nephrologists and cardiologists.

BACKGROUND: Mortality and morbidity from cardiovascular disease are high in patients with end-stage renal disease (ESRD). The cardiovascular profile of patients with ESRD may differ from that of the general population. We examined how nephrologists and cardiologists differ in managing hypertension and cardiovascular disease in patients with ESRD. METHODS: Seven cases incorporating relevant clinical and echocardiographic findings common to this population were developed based on a chart review of an ESRD population. Each ESRD case incorporated a clinical presentation designed to test for a specific dichotomous response to a common and important clinical problem. Nine nephrology and 7 cardiology faculty members, each paired with a senior clinical fellow from the discipline, were surveyed. RESULTS: Nephrologists were less likely than cardiologists to initiate beta-blockade in patients with echocardiographic evidence of regional wall motion abnormalities if there was no history of coronary artery disease (CAD; P < 0.01). In patients with known CAD, cardiologists were more likely than nephrologists to intensify antihypertensive therapy, even in the setting of a history of fractures associated with orthostatic hypotension (P < 0.02). Decision making did not differ between subspecialists in the management of left ventricular hypertrophy, congestive heart failure, or diastolic dysfunction. CONCLUSION: Nephrologists and cardiologists differ in their management of hypertension in the presence of ischemic heart disease in the ESRD population. Only limited data specific to the ESRD population are available to assess which approach is superior. The discipline-driven differential management approaches observed emphasize the need for better evidence-based management strategies for this population.

Accidental Falls↗

Nutrition, lipids, and cardiovascular disease.

The evolving epidemic of cardiovascular disease in many newly industrialized societies will bankrupt their health care systems and reduce the available resources for other health priorities. Therefore, the prevention of this epidemic, or at least slowing the increase, is of the highest priority. The development of coronary heart disease (CHD) is an example of a common source epidemic due to increased consumption of saturated fat and cholesterol, low intakes of polyunsaturated fat, and increasing obesity. Hypertension, cigarette smoking, and diabetes mellitus contribute to risk of disease. The prevention of atherosclerosis beginning in young adults is of paramount importance. Careful monitoring of the evolving epidemic of CHD, including noninvasive evaluation of atherosclerosis, is important. A high-risk approach is very successful but expensive.

Cardiovascular Diseases↗