E. T. Lee

Relations of Left Ventricular Mass to Fat-Free and Adipose Body Mass The Strong Heart Study

BACKGROUND It is unclear whether increased left ventricular (LV) mass in overweight individuals is related to their adiposity or to greater fat-free mass (FFM). METHODS AND RESULTS We compared echocardiographic LV mass to FFM and adipose body mass by bioelectric impedance and to anthropometric measurements in 3107 American Indian participants in the Strong Heart Study. In men and women, the relations of LV mass and FFM (r=0.37 and 0.38, P<0.001) were closer (P<0.05 to <0.001) than they were with adipose mass, waist/hip ratio, body mass index, systolic blood pressure, height, or height2.7. Regression analyses showed that in men LV mass had the strongest independent relation with FFM, followed by systolic blood pressure and age (all P<0.001); in women, LV mass was related to FFM more strongly than it was to systolic blood pressure, age (all P<0. 001), and diabetes (P=0.012). Adipose mass had no independent relation to LV mass. When waist/hip ratio or body mass index were substituted for adipose mass, LV mass was independently related to FFM (P<0.001) and body mass index (P=0.02) but not to waist/hip ratio in men and was independently related to FFM and waist/hip ratio (both P<0.001) but not to body mass index in women. Using 97.5 percentile gender-specific partitions for LV mass/FFM in reference individuals, we found that LV hypertrophy occurred in 20.8% of Strong Heart Study participants with hypertension, overweight, or diabetes compared with 10.5% and 16.7% by LV mass indexed for body surface area or height2.7. CONCLUSIONS LV mass is more strongly related to FFM than to adipose mass, waist/hip ratio, body mass index, or height-based surrogates for lean body weight; LV mass/FFM criteria may increase sensitivity to detect LV hypertrophy.

Risk factors, ethnic differences and mortality associated with lower-extremity gangrene and amputation in diabetes. The WHO Multinational Study of Vascular Disease in Diabetes.

Abstract.Aims/hypothesis: We aimed to examine geographic differences, risk factors and mortality associated with amputation. Methods: Data from 10 of the original 14 centres of the WHO Multinational Study of Vascular Disease in Diabetes were used. This included 3443 men and women aged 35 to 55 years at baseline. Results: Incidences of amputation, adjusted for sex and duration in Type I (insulin-dependent) diabetes mellitus, were 31.0, 8.2, 3.5 and 1.0 per 1000 person years in the American Indian, Cuban, European and East Asian centres respectively. In Type II (non-insulin-dependent) diabetes mellitus, incidences of amputation were 9.7, 2.0, 2.5 and 0.7 per 1000 person years in the American Indian, Cuban, European and East Asian centres respectively. Key risk factors for amputation included glucose, triglyceride, and retinopathy, and were similar for American Indians and Europeans. The age, duration and sex adjusted relative risk for amputation in American Indians compared with Europeans was 11.48 (95 % CI 3.56, 36.98) in Type I diabetes and 3.86 (95 % CI 2.36, 6.32) in Type II diabetes. Adjusting for heart disease, retinopathy, proteinuria, glucose, blood pressure and triglyceride attenuated these relative risks to 10.83 (95 % CI 3.20, 36.65) and 3.15 (1.91, 5.20) in Type I and Type II diabetes respectively. Amputation doubled mortality rates in all groups. Conclusion/interpretation: Vascular complications and their risk factors are themselves risk factors for amputation in both Type I and Type II diabetes and are common to several geographical regions worldwide. However, reasons for differences between geographical regions and the degree to which different health care systems could be responsible is not clear. [Diabetologia (2001) 44 [Suppl 2]: S 65–S 71]

Follow-up of the WHO multinational study of vascular disease in diabetes: general description and morbidity

Abstract.Aims: The incidence of retinal, renal and cardiovascular complications and their relation to baseline risk factors was documented in this follow-up study of 10 of the 14 original centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Methods: The incidence of specified items of vascular disease and some associated risk factors was ascertained after 7 to 9 years (11–12 years in Oklahoma, USA) follow-up, re-using baseline examination methodology in 3165 patients (66.9 %) and, through secondary information in 717 (15.2 %) of the 4729 original patients, of whom 540 (11.4 %) had died and 307 (6.5 %) were untraceable. Results: During follow-up, approximately one third of the patients developed hypertension and one third started insulin. Coronary heart disease incidence varied 10 to 20-fold among centres as did limb amputation rates. Inter-centre differences in incident retinopathy and severe visual impairment were smaller but incident clinical proteinuria and renal failure varied markedly. Vascular disease incidence of all categories was high in Native Americans though coronary heart disease incidence was relatively low in Pima Indians and absolutely low in Hong Kong and Tokyo patients. Specific vascular events and their relation with baseline risk factors are analysed in accompanying papers, summarised in the Epilogue. Conclusion/interpretation: These 10 centres reported very different incidence rates of vascular complications. Observer variation, selection biases and competing causes of mortality contributed to these differences but their validity is supported by the more objective outcome indicators. The following papers also suggest that baseline factors such as raised arterial pressure, cholesterol and fasting glucose (in the centres where it was measured) were important and potentially reversible predictors of risk. [Diabetologia (2001) 44 [Suppl 2]: S 3–S 13]

Risk factors for renal failure: the WHO Multinational Study of Vascular Disease in Diabetes.

Abstract.Aims/hypothesis: We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. Methods: Risk factors for renal failure were examined in 3558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Results: In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years ( ± 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. Conclusion/interpretation: We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure. [Diabetologia (2001) 44 [Suppl 2]: S 46–S 53]

The appearance of retinopathy and progression to proliferative retinopathy: the WHO multinational study of vascular disease in diabetes

Abstract.Aims/hypothesis: We aimed to estimate incidences of any retinopathy and proliferative diabetic retinopathy (PDR) by direct ophthalmoscopy and relate them to baseline risk factors in re-examined diabetic survivors from 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes. Methods: After a mean follow-up of 8.4 years (11.7 years in Oklahoma), 2877 (71.6 %) survivors were resubmitted to standardised direct ophthalmoscopy as at baseline. The presence of any retinopathy and PDR were recorded at each centre and their incidence estimated in those without retinopathy and PDR at baseline. The independent associations of these incidences with baseline risk factors are expressed as odds ratios derived from multiple logistic regression analyses, within individual centres (which included fasting plasma glucose in 8 and triglyceride in 5) and in pooled data. Results: Of the 4662 original patients, 465 (10.4 %) of those without and 77 (43.0 %) of those with baseline PDR had died (p < 0.001). Any retinopathy was newly reported at follow-up in 47.7 % and PDR in 9.7 % of those free of them at baseline, with reported incidences varying substantially among centres. Incident retinopathy appeared earlier in the known course of diabetes but incidence rates rose more slowly with duration in patients with Type II (non-insulin-dependent) diabetes mellitus than in those with Type I (insulin-dependent) diabetes mellitus. In pooled data and in some individual centres, any retinopathy incidence gave significantly positive odds ratios with age, diabetes duration, systolic pressure, plasma cholesterol, BMI, insulin treatment and proteinuria, and with fasting plasma glucose in the centres where it was measured. Positive odds ratios for PDR were similarly obtained for age, duration, insulin treatment, cholesterol, proteinuria and fasting glycaemia. Smoking status odds ratios were negative for both outcomes. Conclusion/interpretation: Incidence of ophthalmoscopically ascertained any retinopathy varied about twofold and of PDR about threefold among centres. Although, in part attributable to differences between observers, variation in incidence in all centres and in some cases within centres was associated with a number of baseline risk factors. Such associations are not likely due to observer variation or selection biases and emerged despite the imprecision of clinical ophthalmoscopy. Improved detection and control of these risk factors should reduce the impact of diabetic retinopathy and its consequences. [Diabetologia (2001) 44 [Suppl 2]: S 22–S 30]

Metabolic syndrome and left ventricular hypertrophy in the prediction of cardiovascular events: the Strong Heart Study.

BACKGROUND AND AIMS Metabolic syndrome (MetS) is associated with increased prevalence of echocardiographic LV hypertrophy (LVH), a potent predictor of cardiovascular (CV) outcome. Whether MetS increases risk of CV events independently of presence of LVH has never been investigated. It is also unclear whether LVH predicts CV risk both in the presence and absence of MetS. METHODS AND RESULTS Participants in the 2nd Strong Heart Study examination without prevalent coronary heart disease, congestive heart failure or renal insufficiency (plasma creatinine >2.5mg/dL) were studied (n=2758; 1746 women). MetS was defined by WHO criteria. Echocardiographic LV hypertrophy was defined using population-specific cut-point value for LV mass index (>47.3g/m(2.7)). After controlling for age, sex, LDL-cholesterol, smoking, plasma creatinine, diabetes, hypertension and obesity, participants with MetS had greater probability of LVH than those without MetS (OR=1.55 [1.18-2.04], p<0.002). Adjusted hazard of composite fatal and non-fatal CV events was greater when LVH was present, in participants without (HR=2.03 [1.33-3.08]) or with MetS (HR=1.64 [1.31-2.04], both p<0.0001), with similar adjusted population attributable risk (12% and 14%). After adjustment for LVH, risk of incident CV events remained 1.47-fold greater in MetS (p<0.003), an effect, however, that was not confirmed when diabetic participants were excluded. CONCLUSION LVH is a strong predictor of composite 8-year fatal and non-fatal CV events either in the presence or in the absence of MetS and accounts for a substantial portion of the high CV risk associated with MetS.

Vascular disease prevalence in diabetic patients in China : standardised comparison with the 14 centres in the WHO multinational study of vascular disease in diabetes

Abstract.Aims/hypothesis: Rates of vascular complications of diabetes in a cohort of mainland Chinese patients with diabetes, ascertained and examined by similar methodology, are compared with those of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Methods: The standardised procedures carried out in the WHO MSVDD were followed in assembling and examining a Chinese cohort of 447 diabetic patients recruited in Beijing and Tianjin [2]. Results: Compared with the WHO MSVDD centres, the Chinese cohort was slightly older, had a shorter duration of known diabetes and had fewer insulin-treated patients. Arterial pressure, total blood cholesterol and body mass index were substantially lower. Large vessel disease rate for age, sex and duration adjusted data (17.9 %) was about half that of the combined WHO MSVDD centres (33.5 % p < 0.001). However, retinopathy (47.4 % vs 35.8 % p < 0.001) and proteinuria (57.1 vs 24.9 % p < 0.001) rates were significantly higher. Conclusion/interpretation: Relatively low arterial pressures and blood cholesterol are likely contributors to the notably low arterial disease rates in this Chinese diabetic cohort; they reflect low rates in the Chinese mainland general population and resemble the Tokyo and Hong Kong centres of the WHO MSVDD. The high rates of retinopathy and proteinuria could relate to later diagnosis, degree of hyperglycaemia and/or increased susceptibiltiy to microangiopathy. [Diabetologia (2001) 44 [Suppl 2]: S 82–S 86]

Arsenic Exposure, Arsenic Metabolism, and Incident Diabetes in the Strong Heart Study

OBJECTIVE Little is known about arsenic metabolism in diabetes development. We investigated the prospective associations of low-moderate arsenic exposure and arsenic metabolism with diabetes incidence in the Strong Heart Study. RESEARCH DESIGN AND METHODS A total of 1,694 diabetes-free participants aged 45–75 years were recruited in 1989–1991 and followed through 1998–1999. We used the proportions of urine inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) over their sum (expressed as iAs%, MMA%, and DMA%) as the biomarkers of arsenic metabolism. Diabetes was defined as fasting glucose ≥126 mg/dL, 2-h glucose ≥200 mg/dL, self-reported diabetes history, or self-reported use of antidiabetic medications. RESULTS Over 11,263.2 person-years of follow-up, 396 participants developed diabetes. Using the leave-one-out approach to model the dynamics of arsenic metabolism, we found that lower MMA% was associated with higher diabetes incidence. The hazard ratios (95% CI) of diabetes incidence for a 5% increase in MMA% were 0.77 (0.63–0.93) and 0.82 (0.73–0.92) when iAs% and DMA%, respectively, were left out of the model. DMA% was associated with higher diabetes incidence only when MMA% decreased (left out of the model) but not when iAs% decreased. iAs% was also associated with higher diabetes incidence when MMA% decreased. The association between MMA% and diabetes incidence was similar by age, sex, study site, obesity, and urine iAs concentrations. CONCLUSIONS Arsenic metabolism, particularly lower MMA%, was prospectively associated with increased incidence of diabetes. Research is needed to evaluate whether arsenic metabolism is related to diabetes incidence per se or through its close connections with one-carbon metabolism.

Relation of generalized and central obesity to cardiovascular risk factors and prevalent coronary heart disease in a sample of American Indians: the Strong Heart Study.

OBJECTIVE: To examine the hypothesis linking measures of obesity including body mass index (BMI), waist circumference (waist) and percentage body fat to coronary heart disease (CHD) prevalence and its risk factors in American Indians.DESIGN: The Strong Heart Study assesses the prevalence of CHD and its risk factors in American Indians in Arizona, Oklahoma and South/North Dakota. Participants underwent a physical examination and an electrocardiogram; anthropometric and blood pressure measurements were taken, as were measurements of glucose, lipoproteins, fibrinogen, insulin, hemoglobin A1c and urinary albumin.PARTICIPANTS: Data were available for 4549 men and women between 45 and 74 y of age.MEASUREMENTS: Obesity, measured using body mass index, waist circumference and percentage body fat, was correlated with prevalent CHD and its risk factors.RESULTS: More than 75% of participants were overweight (BMI>25 kg/m2). Measures of obesity were greater in women than in men, in younger than in older participants, and in participants with diabetes than in nondiabetic participants. CHD risk factors were associated with measures of obesity but, except for insulin concentration, changes in metabolic variables with increasing obesity were small. Associations were not stronger with waist than with BMI. The prevalence of CHD in those whose BMI and/or waist measurements lay in the lowest and highest quintiles, by gender and diabetic status, was similar.CONCLUSIONS: Although CHD risk factors are associated with obesity in American Indians, distribution of obesity (ie waist) is no more closely related to risk factors than is generalized obesity (ie BMI), and changes in CHD risk factors with obesity were small. Thus, the relations among obesity, body fat distribution and CHD risk may differ in this population.

Evidence for joint action of genes on diabetes status and CVD risk factors in American Indians: the Strong Heart Family Study

OBJECTIVES: Previous research among American Indians of the strong heart family study (SHFS) has demonstrated significant heritabilities for CVD risk factors and implicated diabetes as an important predictor of several of the phenotypes. Moreover, we recently demonstrated that genetic effects on CVD risk factors differed in diabetic and nondiabetic individuals. In this paper, we investigated whether a significant genetic influence on diabetes status could be identified, and whether there is evidence for joint action of genes on diabetes status and related CVD risk factors.METHODS AND RESULTS: Approximately 950 men and women, age 18 or older, in 32 extended families, were examined between 1997 and 1999. We estimated the effects of genes and environmental covariates on diabetes status using a threshold model and a maximum likelihood variance component approach. Diabetes status exhibited a residual heritability of 22% (h2=0.22). We also estimated the genetic and environmental correlations between diabetes susceptibility and eight risk factors for CVD. All eight CVD risk factors displayed significant genetic correlations with diabetes status (BMI (ρG=0.55), fibrinogen (ρG=0.40), HDL-C (ρG=−0.37), ln triglycerides (ρG=0.65), FAT (ρG=0.38), PAI-1 (ρG=0.67), SBP (ρG=0.57), and WHR (ρG=0.58)). Three of eight traits (HDL-C (ρE=−0.32), ln triglycerides (ρE=0.33), and fibrinogen (ρE=0.20)) displayed significant environmental correlations with diabetes status.CONCLUSIONS: These findings suggest that in the context of a high prevalence of diabetes, still unidentified diabetes genes may play an important role in influencing variation in CVD risk factors.