Reassessment of cardiovascular risk in diabetes

PURPOSE OF REVIEW: To review recent trials and reassess cardiovascular risk in people with diabetes. RECENT FINDINGS: Recent clinical trials have tended to focus on lower-risk participants with diabetes who have had event rates considerably lower than participants in the early lipid trials. Statin studies have generally shown benefit in those without cardiovascular disease and at lower levels of low-density lipoprotein cholesterol. Results of fibrate and glitazone studies have been mixed; the question of benefit among statin-treated patients remains unanswered. Investigators failed to confirm the benefits of glucose control observed in the original Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction study possibly due to study design issues. Epidemiologic follow-up of the Diabetes Control and Complications Trial showed sustained benefit of glucose control. A number of studies have shown the benefit of inpatient control of blood glucose. We await the results of ongoing blood pressure trials and other ongoing trials, which should provide much new information. A conceptual model of cardiovascular risk for people with diabetes mellitus based on the UK Prospective Diabetes Study outcomes model is discussed. SUMMARY: The majority of adults with diabetes have a substantially greater risk compared with those without diabetes and a small percentage has very high risk. A minority of individuals may have considerably lower 10-year risk.     

Relationship between trajectories of trunk fat mass development in adolescence and cardiometabolic risk in young adulthood

To examine developmental trajectories of trunk fat mass (FM) growth of individuals categorized as either low or high for cardiometabolic risk at 26 years, a total of 55 males and 76 females from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991–2007) were assessed from adolescence (11.5 ± 1.8 years) to young adulthood (26.2 ± 2.2 years) (median of 11 visits per individual) and had a measure of cardiometabolic risk in young adulthood. Participants were categorized as low or high for blood pressure and cardiometabolic risk as adults using a sex‐specific median split of continuous standardized risk scores. Individual trunk FM trajectories of participants in each risk group were analyzed using multilevel random effects models. Males and females in the high blood pressure group had significantly steeper (accelerated) trajectories of trunk FM development (0.61 ± 0.14 and 0.52 ± 0.10 log g, respectively) than those in the low blood pressure group for females in the high cardiometabolic risk group trajectory of trunk FM was significantly steeper (0.52 ± 0.10 log g) than those females in the low cardiometabolic risk group. Dietary fat was positively related (0.01 ± 0.003 g/1,000 kcal) and physical activity negatively related (?0.16 ± 0.05 physical activity score) to trunk FM development in males. Young adults with high cardiometabolic risk, compared to low, have greater trunk FM as early as 8 years of age, which supports the need for early intervention.     

Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants.

BACKGROUND: Intensive medical care of women with diabetes has reduced their risks of bearing infants with congenital anomalies. To assess the preventive potential of preconceptional care, the data of a population-based study of cardiovascular malformations (CVM) were analyzed to determine the morphogenetic specificity of maternal diabetes risks, the morbidity and mortality of the infants, and maternal characteristics that might affect these risks. METHODS: The Baltimore-Washington Infant Study was a case-control study (1981-1989) that included all live born infants with confirmed CVM; control infants were a representative sample of the birth cohort. A questionnaire administered in home visits recorded parental information on social, medical, occupational, and environmental factors. For these analyses of preconceptional diabetes risks, the case group excluded chromosomal and mendelian disorders and was divided into 3 developmental categories and 12 diagnostic groups. RESULTS: Preconceptional maternal diabetes was strongly associated with CVM of early embryonic origin (odds ratio [OR] = 4.7, 95% confidence interval [CI] 2.8-7.9) and with cardiomyopathy (OR = 15.1, 95% CI 5.5-41.3), but not with obstructive and shunting defects (OR = 1.4, 95% CI 0.7-3.0). There was heterogeneity within these developmental categories: among laterality defects, diabetes was associated only with cardiovisceral and atrioventricular discordance (OR = 10.0, 95% CI 3.7-27.0); among outflow tract anomalies, the risk was strongly associated with normally related great arteries (OR = 6.6, 95% CI 3.2-13.3) but not with simple transpositions; and among atrioventricular septal defects, diabetes was associated with the complete but not with the partial forms (OR = 22.8, 95% CI 7.4-70.5). The association in early CVM was strongest among infants with multisystem, predominantly VACTERL, anomalies. All-cause mortality of infants with CVM was 39% among those with diabetic mothers and 17.8% in those with nondiabetic mothers. Deceased infants of diabetic mothers were also more likely to have extracardiac anomalies (P = 0.041), to be born prematurely (P = 0.007), and to have low birth weight (P = 0.011). Multivariate analyses of maternal factors revealed no significant confounders of the diabetes associations. CONCLUSIONS: The evidence of diabetes-induced major cardiac defects is of urgent clinical significance. The effectiveness of early preconceptional care in the prevention of congenital anomalies has been demonstrated repeatedly.     

Primary hyperlipoproteinemia in childhood and adolescence: identification and treatment of persons at risk for premature atherosclerosis.

Determination of serum cholesterol values in three populations of children and adolescents, totalling 4013 subjects aged 1 month to 20 years, revealed 16 cases of primary hyperbetalipoproteinemia (overall frequency, 1:251) and led to the detection of the disorder in 12 asymptomatic siblings. The upper limit of normal for serum cholesterol concentration was approximately 200 mg/dl at all ages studied. Dietary treatment was instituted in patients whose serum cholesterol value exceeded this limit and in whom a primary lipid defect was confirmed; the serum cholesterol value decreased in all patients who adhered to the diet. However, since the potential hazards and long-term results of dietary treatment, with or without drug therapy, in growing children are not known, such treatment should be reserved for affected children with a family history of premature atherosclerosis, and follow-up is essential.     

Development of the corpus callosum in childhood,adolescence and early adulthood

The corpus callosum (CC) is the major commissure connecting the cerebral hemispheres and there is evidence of its continuing development into young adulthood [Ann. Neurol. 34 (1993) 71]. Yet, little is known about changes in the size and tissue characteristics of its sub-regions. The sub-regions of the CC (genu, body, isthmus and splenium) are topographically organized to carry interhemispheric fibres representing heteromodal and unimodal cortical brain regions. Studies of the development of each of these sub-regions can therefore provide insights into the time course of brain development. We assessed age-related changes in the size and the signal intensities (SI) of the subregions of the corpus callosum in the Magnetic Resonance Imaging (MRI) scans of a cross-sectional sample of 109 healthy young individuals aged 7-32 years. Age was significantly positively correlated with the size of the callosal sub-regions (with the exception of the isthmus). On the other hand, there was an age-related decrease in SI across all the CC sub-regions. The rates of CC regional size increases appeared to be most pronounced in childhood. By contrast, SI decreases occurred during childhood and adolescence but reached an asymptote during young adulthood. Finally, the observed size and SI changes were similar across CC sub-regions. The observed increases in CC size in conjunction with the decreases in signal intensity reflect continued maturation of the structure from childhood through young adulthood. An increase in axonal size may underlie growth in the size of the CC during childhood. The continued decrease in the CC signal intensity during adolescence may in addition be related to ongoing maturation of the axonal cytoskeleton. CC maturational changes appeared synchronous across sub-regions suggesting parallel maturation of diverse brain regions during childhood and adolescence.     

Familial genetic risk factors in premature cardiovascular disease: a family study

Cardiovascular disease (CVD) is closely associated with familial predisposition. The aim of the present study was to investigate predisposing risk factors in the family of a young patient who underwent coronary artery bypass graft surgery due to CVD. The father and uncle of the patient died at an early age due to myocardial infarction. Various stages of CVD were identified in both of the patient’s brothers (28 and 32 years of age). Biochemical tests (fasting blood glucose, lipid profile, urea, creatinine and liver enzymes) and a complete blood count (haemoglobin, haematocrit, white blood cell count, and platelet count) were performed. Physiological coagulation inhibitory factors (protein C, protein S, and antithrombin III), prothrombotic genetic risk factors (factor V Leiden, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase A1C and C6T, angiotensin-converting enzyme, β-fibrinogen, glycoprotein IIIa and factor XIII) and homocysteine levels were evaluated in all cases. Defects were observed in many genetic factors and in the systems regulated by these factors. The results were compatible with those reported in the literature. In conclusion, it is possible to determine a specific family history in young adults with CVD. From this perspective, the emergence of more serious CVD may be prevented by providing disease-related information to the other family members and implementing preventive measures.     

Effect of the timing of weight cycling during adulthood on mortality risk in overweight and obese postmenopausal women

Inconsistent results exist for whether or not weight cycling (WgtC) and weight variability (WgtV) increase mortality risk. The aim of this study was to examine the effect of WgtC and WgtV during adulthood on mortality risk. Data was obtained from the Women's Health Initiative (WHI) observational study (OS) dataset, acquired from the National Heart, Lung and Blood Institute (N = 47,473 overweight and obese women; age 50–79 years). Women were categorized (stable; WgtV: weight‐gainer or loser; or WgtC) based on weight changes during early (18–35 years), mid (35–50 years), and late (50 years to current age) adulthood. Those with weight changes of <5% during all three time‐periods were classified as being stable‐weight. Weight‐gainers were those with at least one period of weight‐gain (≥5%) without a period of weight‐loss (≥5%), and weight‐losers were those with at least one period of loss without a period of gain during all time‐periods. Those who experienced both a period of weight‐gain and loss (≥5%) were categorized as WgtC. Compared to stable‐weight individuals, WgtC and WgtV across adulthood were not significantly associated with mortality risk when the age‐period of weight change was not considered. However, when considering the age period, increased mortality risk was observed for every 5 kg of weight‐gain during early (hazard ratio (HR) = 1.04 (1.00–1.07)) or mid‐adulthood (HR = 1.05 (1.02–1.08)), or for every 5 kg of weight‐loss since mid (HR = 1.12 (1.01–1.24)) or late‐adulthood (HR = 1.12 (1.04–1.20)). In conclusion, merely investigating WgtC and WgtV by weight changes across adulthood may not be sufficient to fully describe mortality risk, and the age at which the weight change occurred might be as important to consider.     

Born small for gestational age: increased risk of type 2 diabetes,hypertension and hyperlipidaemia in adulthood

The metabolic and cardiovascular complications associated with reduced fetal growth have been identified in the past 10 years. These include cardiovascular disease and the insulin resistance syndrome, comprising dyslipidaemia and impaired glucose tolerance or type 2 diabetes, and they appear to result from the initial development of insulin resistance. Although the mechanism underlying the development of insulin resistance associated with reduced fetal growth remains unclear, there is some evidence that adipose tissue plays a key role. Over the past decade, several hypotheses have been proposed to explain this unexpected association. Each points to either a detrimental fetal environment, genetic susceptibility or an interaction between the two. Although yet to be confirmed, the hypothesis suggesting that the association could be the consequence of genetic-environmental interactions is at present the most attractive.     

Association of cardiovascular disease risk factors with socioeconomic position during childhood and during adulthood.

OBJECTIVE: To investigate strength of associations between risk factors for cardiovascular disease and socioeconomic position during childhood and adulthood. DESIGN: Cross sectional analysis of status of cardiovascular risk factors and past and present social circumstances. SUBJECTS: 5645 male participants in the west of Scotland collaborative study, a workplace screening study. MAIN OUTCOME MEASURES: Strength of association between each risk factor for cardiovascular disease (diastolic blood pressure, serum cholesterol concentration, level of recreational physical exercise, cigarette smoking, body mass index, and FEV1 score (forced expiratory volume in one second as percentage of expected value) and social class during childhood (based on father''s main occupation) and adulthood (based on own occupation at time of screening). RESULTS: All the measured risk factors were significantly associated with both father''s and own social class (P < 0.05), apart from exercise and smoking (not significantly associated with father''s social class) and body mass index (not significantly associated with own social class). For all risk factors except body mass index, the regression coefficient of own social class was larger than the regression coefficient of father''s social class. The difference between the coefficients was significant for serum cholesterol concentration, cigarette smoking, body mass index, and FEV1 score (all P < 0.001). CONCLUSIONS: Subjects'' status for behavioural risk factors (exercise and smoking) was associated primarily with current socioeconomic circumstances, while status for physiological risk factors (serum cholesterol, blood pressure, body mass index, and FEV1) was associated to varying extents with both past and present socioeconomic circumstances.     

Behavioral and neuroendocrine consequences of social subjugation across adolescence and adulthood

BACKGROUND: Social subjugation is a very significant and natural stressor in the animal kingdom. Adult animals defeated and subjugated during establishment of dominance hierarchies or territorial encounters can be highly submissive in future agonistic interactions. While much is know about the biological and behavioral consequences of winning and losing fights in adulthood, little is known about adolescence; a developmental period noted for impulsivity and heightened agonistic behavior. The present studies were undertaken to determine if the behavioral and neuroendocrine consequences of social subjugation are comparable in adolescent versus adult Syrian golden hamsters (Mesocricetus auratus). Male siblings were studied from adolescence into adulthood following exposure to counterbalanced episodes of either a benign stressor, i.e., isolation in a novel cage, or the more severe stressor of social subjugation. RESULTS: As adults, hamsters with a history of social subjugation in adolescence show high levels of aggression toward intruders as compared to siblings subjugated in adulthood. Sibling controls subjugated in adulthood are highly submissive with little or no aggressive behavior. However, when subjugated in adulthood, hamsters with the earlier history of subjugation are no different than their sibling controls, i.e., adult subjugation promotes submissive behavior. Sexual motivation is high in adult hamsters with adolescent subjugation and testosterone levels remained stable over adulthood. In contrast, sibling controls subjugated in adulthood show lower levels of sexual motivation and reduced levels of testosterone. Release of cortisol during agonistic encounters is blunted in animals subjugated in adolescence but not adulthood. Measures of anxiety are reduced in hamsters with adolescent subjugation as compared to their sibling controls. CONCLUSION: These data demonstrate a pronounced difference in behavior and neuroendocrinology between adolescent and adult hamsters in their response to social subjugation and suggest adolescence is a resilient period in development.     

Temporal changes and rural-urban differences in cardiovascular disease risk factors and mortality in China.

We summarize several studies, from the last 10 years, of temporal changes and rural-urban differences in the risk factors of cardiovascular disease (CVD) in China to indicate the influences of economic modernization. Two national blood pressure surveys have shown that the prevalence of hypertension increased from 5.1% to 7.7% between 1958-1959 and 1979-1980. Throughout China hypertension is more prevalent in urban areas than in rural areas. Within the Shanghai region body mass index, blood pressure, and total serum cholesterol were higher in urban districts than in rural areas. Rural-urban differences in lipid levels were also found in the Beijing and Guangzhou regions. A related four-year followup study showed that total serum cholesterol and triglycerides increased markedly in both urban and rural areas of Guangzhou. In Shanghai part-time farmers who worked in factories had a higher age-adjusted prevalence of definite hypertension than farmers who worked full-time in the fields (5.0% versus 2.3%). In a prospective study in Wuhan a new productivity-based salary system was associated with increased serum cholesterol and blood pressure. Age-adjusted CVD mortality increased from 1973 to 1982 in a rapidly industrializing county in the Shanghai metropolitan region. The results from several studies indicate that China is undergoing the expected increase in modernization-related CVD risk factors and mortality, especially in urban metropolitan regions.     

Arterial function in youth: window into cardiovascular risk.

Noninvasive measures of arterial function, such as intima-media thickness (IMT), endothelial function, and arterial stiffness are associated with and are prognostic of cardiovascular events in adults. Postmortem evidence, however, has established that the atherosclerotic process starts in childhood. Furthermore, cardiovascular morbidities in childhood disrupt arterial health and may lead to adverse outcomes in adulthood. Thus it is important to examine the developmental changes in IMT, endothelial function, and arterial stiffness in healthy youth in contrast to the arterial health profile of youth with cardiovascular morbidities and to examine the effect of lifestyle interventions. In healthy youth, IMT may increase slightly, arterial stiffness increases, but there is no change in endothelial function from 5 to 20 years of age. In youth with cardiovascular risk factors there are larger increases in IMT and arterial stiffness, and reductions in endothelial function compared with healthy youth. The reduced arterial function in youth with cardiovascular risk factors may be related to the atherosclerotic process. Exercise and physical activity appear to exert a protective effect on arterial function, and exercise training can improve arterial function in children with cardiovascular risk factors. Furthermore, although diet alone can improve arterial function in children, the combination of exercise and diet appears to be more effective than either intervention alone. Future studies need to focus on the mechanism by which exercise and diet improve arterial function, the most effective types of diet and exercise, and if intervening in childhood leads to favorable outcomes in adulthood.