An affected pedigree member analysis of linkage between the dopamine D2 receptor gene TaqI polymorphism and obesity and hypertension.

BACKGROUND: Dopamine modulates a variety of physiological functions including natriuresis and satiety. We have previously reported that the TaqI polymorphism of the dopamine D2 receptor (DD2R) gene is associated with both blood pressure and obesity indices in a normoglycaemic Hong Kong Chinese population. In this study, we present evidence confirming the linkage between this gene polymorphism, obesity and hypertension. METHODS: Two hundred and seventy-four siblings from 96 normoglycaemic hypertensive families were recruited, including 133 who were hypertensive. Central obesity was defined as a waist-to-hip ratio of > or = 0.9 and > or = 0.85 in males and females, respectively, and was identified in 99 of the siblings. The DD2R gene TaqI polymorphism was identified with a polymerase chain reaction based restriction fragment length polymorphism protocol. The affected pedigree member (APM) linkage analysis (sib-pair program, version 0.99.9, by D.L. Duffy) was used to assess for linkage between this gene polymorphism, obesity and hypertension in 73 families with siblings discordant for hypertension. RESULTS: The A1 allele frequencies were similar in the 133 hypertensive, and 141 normotensive siblings, including the 99 centrally obese siblings at 0.431, 0.421 and 0.418, respectively. APM linkage analysis suggested that the DD2R gene TaqI polymorphism had evidence of linkage with blood pressure (T = -1.86, P = 0.013), as well as with obesity (T = -1.58, P = 0.007). CONCLUSION: Our data in normoglycaemic Hong Kong Chinese supports that the DD2R gene TaqI polymorphism is a marker associated with the pathogenesis of obesity and hypertension.

Randomized, controlled, parallel-group comparison of ambulatory and clinic blood pressure responses to amlodipine or enalapril during and after treatment in adult chinese patients with hypertension.

BACKGROUND: Few studies have examined the relative efficacy and tolerability of antihypertensive drug classes in Chinese populations. OBJECTIVE: This study compared the efficacy, tolerability, and duration of antihypertensive effect of amlodipine besylate and enalapril in Chinese patients with hypertension, including elderly patients with isolated systolic hypertension. METHODS: This randomized, double-blind, double-dummy, parallel-group dose-titration study was conducted at the Department of Medicine and Therapeutics, Chinese University of Hong Kong. Chinese patients aged 18 to 80 years with primary hypertension were enrolled. After a 4-week placebo run-in period, patients were randomly assigned to receive active oral, once-daily treatment with amlodipine (5 mg) or with enalapril (5 mg) for 14 weeks. Treatment doses were titrated at weeks 4 and 8 if necessary according to blood pressure (BP) response and if the dose had been tolerated. Patients also underwent 24-hour ambulatory BP monitoring (ABPM) at the end of the placebo run-in, after the first and last doses of active treatment, and 48 hours after discontinuation of treatment to determine the duration of drug action and to mimic the effect of 2 missed doses. RESULTS: Eighty patients were recruited for the study (26 men, 54 women; mean [SD] age, 60.5 [11.6] years) (40 patients per group). Thirty-seven patients in each group completed the active treatment phase. Baseline trough BPs were similar: 167.7 (15.0)/94.6 (9.7) mm Hg in the amlodipine group and 168.6 (11.9)/93.4 (9.5) mm Hg in the enalapril group. After 14 weeks of treatment, amlodipine (mean [SD] final dose, 6.3 [2.3] mg) produced greater reductions than enalapril (mean [SD] final dose, 13.3 [6.6] mg) in trough BP (-20.8 [13.2]/-9.2 [9.0] vs -5.5 [14.9]/-3.2 [10.6] mm Hg, respectively; P < or = 0.01). Most of the effect of amlodipine persisted for 72 hours after the last dose (-18.9 [14.6]/-11.1 [11.7] mm Hg), but enalapril had no significant antihypertensive effect at 72 hours (-1.3 [12.3]/-1.8 [9.1] mm Hg). Similar observations were found with ABPM recordings. Cough was reported in 5 patients (12.5%) and 13 patients (32.5%) in the amlodipine and enalapril groups, respectively, but was thought to be treatment related in only 6 patients (15.0%), all in the enalapril group. One of the patients in the enalapril group withdrew from the study because of cough, and 1 patient in the amlodipine group withdrew because of ankle edema.

The renoprotective effects of structured care in a clinical trial setting in type 2 diabetic patients with nephropathy.

BACKGROUND: The RENAAL Study has confirmed the renoprotective effects of Losartan in type 2 diabetes. In this subgroup analysis from the RENAAL Study, we hypothesized that the intensive care received by patients in a clinical trial setting also reduced the rate of decline in renal function through optimization of all risk factors. METHODS: We compared the rate of deterioration in renal function, expressed as the regression coefficient of the monthly serum creatinine (SeCr) reciprocal (beta-1/Cr) in 55 Chinese type 2 diabetic patients before and after entry into the RENAAL Study. RESULTS: Of the 55 patients, 44 had at least three out-patient SeCr measurements both before (2.9+/-2.4 years) and after (3.3+/-0.8 years) entry into the study for evaluation. In the Losartan group (n = 24), the median beta-1/Cr fell from -11.4 x 10(-5) l micro mol(-1) month(-1) before entry into the trial to -4.7 x 10(-5) l micro mol(-1) month(-1) following entry (P = 0.001). The respective figures were -9.1 x 10(-5) and -5.0 x 10(-5) l micro mol(-1) month(-1) (P = 0.01) in the placebo group (n = 20). A decrease in beta-1/Cr was observed in 21 (87.5%) and 14 (70.0%) patients in the Losartan and placebo groups, respectively. Spot urinary albumin-to-creatinine ratio was reduced by 56% (P = 0.001) in the Losartan group but the change was not significant in the placebo group. At the end of the study, patients in both groups had lower blood pressure and better lipid control. The frequency of patient visits to doctors and nurses were doubled. CONCLUSIONS: The rate of renal function decline was significantly reduced in the majority of patients allocated to either Losartan or placebo following entry into the RENAAL study. These results suggest that in patients with diabetic nephropathy, implementation of a structured care protocol in a clinical trial setting facilities intensive treatment of risk factors confering renoprotective effects in addition to those resulting from Losartan treatment.

Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25.

We conducted an autosomal genome scan to map loci for type 2 diabetes in a Hong Kong Chinese population. We studied 64 families, segregating type 2 diabetes, of which 57 had at least one member with an age at diagnosis of 0.59, P(pointwise) < 0.05): chromosome 1 at 173.9 cM (LOD = 3.09), chromosome 3 at 26.3 cM (LOD = 1.27), chromosome 4 at 135.3 cM (LOD = 2.63), chromosome 5 at 139.3 cM (LOD = 0.84), chromosome 6 at 178.9 cM (LOD = 1.91), chromosome 12 at 48.7 cM (LOD = 1.99), and chromosome 18 at 28.1 cM (LOD = 1.00). Simulation studies showed genome-wide significant evidence for linkage of the chromosome 1 region (P(genome-wide) = 0.036). We have confirmed the results of previous studies for the presence of a susceptibility locus on chromosome 1q21-q25 (173.9 cM) and suggest the locations of other loci that may contribute to the development of type 2 diabetes in Hong Kong Chinese.

Increasing insulin resistance contributes to worsening glycaemic and lipid profiles in older Chinese subjects.

OBJECTIVE: To investigate the impact of insulin resistance on cardiovascular risk factors in the elderly. RESEARCH DESIGN AND METHODS: A cross-sectional, community-based study of 225 older Chinese participants (65-74 years, 55.6% female) recruited from community centres for the elderly in Shatin. Anthropometric measures and DXA body fat, blood pressure, insulin sensitivity (fasting insulin, fasting insulin-glucose product, short insulin tolerance test (SITT)), glycaemic (fasting glucose, glycated haemoglobin A1c) and lipid (total, HDL-, and LDL-cholesterol, triglycerides) indices and albuminuria (24h albumin-to-creatinine ratio) were measured. RESULTS: There was a close correlation between the SITT and insulin-glucose product indices of insulin resistance. Decreasing tertiles of insulin sensitivity were associated with increasing indices of glycaemic control, and general and central obesity, including DXA lean and fat mass, albuminuria, and triglycerides, with decreasing HDL-cholesterol. There were no differences in blood pressure or electrolyte levels between these tertile groups. These subjects were more insulin resistant than a group of younger diabetics. CONCLUSIONS: Insulin resistance was associated with indices of obesity and an atherogenic lipid and hyperglycaemic profile and may in part contribute to the high frequency of metabolic syndrome components in these older Chinese subjects.

Effects of protocol-driven care versus usual outpatient clinic care on survival rates in patients with type 2 diabetes.

OBJECTIVE: To determine whether clinical outcomes in patients with type 2 diabetes were improved by protocol-driven care in a Diabetes Centre compared with usual outpatient care. STUDY DESIGN: Descriptive analysis of a prospective cohort. PATIENTS AND METHODS: During a median 7-year observational period, 91 patients with type 2 diabetes and no cardiovascular or renal complications were monitored by a nurse and a diabetologist in a clinical trial setting according to a structured protocol. Another 81 patients with comparable clinical characteristics were monitored by generalists at the medical clinic in the same hospital. Clinical end points, defined as death and cardiovascular and renal events, were evaluated in 1997 by review of case records. RESULTS: Patients receiving structured care had lower mortality (relative risk [RR] = 0.21; 95% confidence interval [CI] = 0.07, 0.65; P = .006) than the usual-care group, as well as a lower incidence of combined clinical end points (RR = 0.43; 95% CI = 0.22, 0.84; P = .01). In the usual-care group, patients who had no monitoring of glycosylated hemoglobin or plasma lipid levels during the entire observational period (8.6%) had a 14.6-fold (P < .01) and 15.7-fold (P < .01) increased risk of death and combined clinical end points, respectively, compared with those who had at least one measurement (60.5%). CONCLUSION: Management by protocol-driven care model improved survival and clinical outcomes in patients with type 2 diabetes. Definitive studies are required to confirm these findings and compare the cost effectiveness of these care models.

Association of two apolipoprotein A-I gene MspI polymorphisms with high density lipoprotein (HDL)-cholesterol levels and indices of obesity in selected healthy Chinese subjects and in patients with early-onset type 2 diabetes.

OBJECTIVE: Previous studies have reported associations between two apolipoprotein A-I (apoA-I) gene MspI polymorphisms (G-75A and C83T) and high density lipoprotein (HDL)-cholesterol and/or apoA-I levels, but have not investigated the relationship with obesity. METHODS: We determined the distribution of these polymorphisms in 482 early-onset (< or = 40 years) Type 2 Chinese diabetics and 167 Chinese selected healthy controls. RESULTS: The -75A and 83T allele frequencies were similar in the diabetic and healthy subjects. In the healthy control subjects, HDL-cholesterol levels were significantly higher in the AA homozygotes than in the GG/GA carriers (1.74 +/- 0.58 vs. 1.45 +/- 0.58 mmol/l, P<0.001). Furthermore, analyses showed a significant relationship between increasing HDL-cholesterol tertiles and the AA genotype frequency in the selected healthy subjects (3.6, 8.9 and 16.1%, P=0.026). For the C83T polymorphism, healthy male CT carriers had higher HDL-cholesterol levels than CC homozygotes (1.71 +/- 0.57 vs. 1.25 +/- 0.30 mmol/l, P=0.001), but this was not found in females. No relationship between these polymorphisms and lipid levels was found in the diabetics, who had a more adverse lipid profile than the selected controls. In the diabetics, but not the controls, in CT carriers compared to CC homozygotes there were lower levels of body mass index (BMI; 23.8 +/- 3.9 vs. 25.4 +/- 4.7 kg/m2, P=0.048) and waist-to-height ratio (0.49 +/- 0.06 vs. 0.52 +/- 0.07, P=0.023), and this relationship was supported by tertile analysis. CONCLUSIONS: The -75AA genotype was associated with higher HDL-cholesterol levels in the selected healthy, but not diabetic, subjects. The 83T allele was associated with greater indices of obesity in the diabetic patients, and with higher HDL-cholesterol in heterozygous healthy male subjects.

Phenotypic heterogeneity and associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in type 2 diabetes.

OBJECTIVE: We investigated the phenotypic features of diabetic microvascular complications and their association with a (CA)(n) microsatellite and a C/T polymorphism at the 5' region of the aldose reductase gene (ALR2) in a consecutive cohort of 738 Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Of the entire patient cohort, 392 were free of diabetes complications, or uncomplicated, 159 had diabetic nephropathy, 66 had diabetic retinopathy, and 121 had both diabetic nephropathy and retinopathy. Nephropathy was defined as urinary albumin excretion rate (AER) >or=20 micro g/min and albumin-to-creatinine ratio >or=3.5 mg/mmol in two urine collections. Retinopathy was defined by the presence of hemorrhages, exudates, laser marks, and fibrous proliferation or by a history of vitrectomy. (CA)(n) and C/T polymorphisms were examined by PCR followed by capillary electrophoresis and digestion with BfaI, respectively. RESULTS: In the whole cohort, patients with diabetic retinopathy (n = 187) had higher blood pressure and lower BMI, while those with diabetic nephropathy (n = 280) had higher blood pressure, waist-to-hip ratio, and lipid profile than those without the respective complications. The z+6 carriers of the (CA)(n) polymorphism were less common in patients with diabetic retinopathy than those without diabetic retinopathy (n = 551) (4.3 vs. 9.3%, P = 0.04). The CT/TT carriers had a higher AER than the CC carriers (30.2 x/divided by 7.2 vs. 21.9 x/divided by 6.9 micro g/min, P = 0.03). Further subgroup analysis was performed after excluding uncomplicated patients with <5 years disease duration. The group with both diabetic nephropathy and retinopathy had higher frequencies of the z-2 allele (25.7 vs. 16.9%, P = 0.03) and T allele (26.4 vs. 18.5%, P = 0.04) and a lower frequency of the z+6 allele (1.7 vs. 5.5%, P = 0.054) than the uncomplicated group. Multiple logistic regression analysis confirmed that z-2 carrying (odds ratio 2.6, 95% CI 1.20-5.83, P = 0.02) and CT/TT genotypes (OR 2.5, 95% CI 1.19-5.19, P = 0.02) were independent predictors for both diabetic nephropathy and retinopathy. CONCLUSIONS: Chinese type 2 diabetic patients exhibited phenotypic differences in terms of risk factors for both diabetic nephropathy and diabetic retinopathy. Both the z-2 allele of (CA)(n) polymorphism and T allele of ALR2 were independently associated with severe diabetic microvascular complications.

The lipoprotein lipase gene HindIII polymorphism is associated with lipid levels in early-onset type 2 diabetic patients.

Lipoprotein lipase (LPL) plays a central role in triglyceride metabolism, and the LPL gene T495G HindIII polymorphism has been associated with variations in lipid levels and heart disease in Caucasians with the more common H+ allele being associated with adverse lipid profiles and increased risk of CHD. We investigated this polymorphism in 785 Chinese subjects with varying components of the metabolic syndrome, including 61.4% with early-onset type 2 diabetes (age at diagnosis < or = 40 years), and 167 healthy control subjects using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. The allele and genotype frequencies were similar in the patients and control subjects. When grouped above or below standard cutoffs for triglyceride levels, the H+ allele was more frequent in hypertriglyceridemic than that in normotriglyceridemic subjects in the total population (81.5% v 76.1%) and early-onset type 2 diabetics (84.4% v 77.4%, both P <.05). Moreover, H+H+ carriers had significantly higher plasma triglyceride and lower high-density lipoprotein (HDL)-cholesterol levels when compared to subjects with the H- allele in the total population, and in patients with early-onset diabetics (both P <.05). In the total population and the early-onset diabetic patients, this relationship was confined to males when gender was considered. We conclude that the H+ allele of the LPL gene HindIII polymorphism is associated with higher plasma triglyceride and lower HDL-cholesterol levels in Chinese patients with early-onset diabetes.

Association of the D8S282 marker near the lipoprotein lipase gene locus with systolic blood pressure in healthy Chinese subjects.

OBJECTIVE: To investigate the association between the marker D8S282 near the lipoprotein lipase (LPL) gene locus, and blood pressure, anthropometric and biochemical parameters in 229 healthy Chinese subjects. METHOD Genotyping was performed using an automated DNA sequencer and the Base ImageIR software. Eight different alleles were identified (272-286 bp) resulting in 15 genotypes in our population. We investigated the association between the common (28.8%) 278 bp allele and the anthropometric and biochemical parameters. RESULTS: In a tertile analysis, the frequency of the 278 bp allele increased linearly ( P = 0.003) with increasing systolic blood pressure (SBP). The relationship was most evident in the females ( n = 141); SBP was higher in homozygotes for the 278 bp allele (117 +/- 10 mmHg, = 12) than those without this allele (109 +/- 9 mmHg, = 77, 0.05) and was gene-dose dependent, and this difference was more significant after adjusting for age (P = 0.004). No relationship between the locus and the anthropometric or biochemical parameters investigated was observed. CONCLUSION: The D8S282 marker near the LPL gene locus contributes to the variance of SBP in healthy Hong Kong Chinese subjects, particularly in females.

Averaging improves the quality of impedance stroke volume measurements during the head up tilt test.

OBJECTIVES: To assess the improvement in quality following averaging data from two or more tilts in the stroke volume (SV) response curve during a head-up tilt test. METHODS: Ten adult male subjects were tilted head-up to 55 degrees four times. They were kept head-up for 3-minutes with intervening rests of 3-minutes. Impedance measurements were recorded by the RheoCardioMonitor every 10-seconds. The percentage changes in impedance variables with tilting and coefficients of variability (CV) were calculated. The SV data were divided into four single tilt response curves, which were used to assess the variability of the data when these tilts were analyzed separately, in pairs or in triplets. Confidence intervals reflecting this variability were estimated. RESULTS: Head-up tilting resulted in a mean (SD) decrease in SV of 31 (11)%. Significant variability existed between SV readings (CV = 8 (2)%). Averaging improved the resolution of the wavelets and in most subjects (7 out of 10) allowed dynamic and static phases of the response to be identified. Upper confidence intervals (mean (range)) were reduced from 15 (10-23)% for single wavelets to 8 (3-10)% for pairs to 5 (3-8)% for triplets. CONCLUSIONS: Impedance measurements can be very variable, making the assessment of SV changes during a head-up tilt test difficult. By averaging the data from several tilts one can improved the quality of the SV wavelet sufficiently to identify important postural changes.

A comparison of two impedance cardiographs using head-up tilting and trend analysis.

OBJECTIVES: To compare the performances of two impedance cardiographs, the RheoCardioMonitor (RCM) and the BoMed NCCOM3, using trend analysis. This involved a series of head-up tilts, a simulation of the stroke volume (SV) and cardiac output (CO) response, calculation of prediction errors and cumulative sums (Cusum). METHODS: Eight healthy male volunteers, aged 27-37 years, were tilted on four occasions to angles of 55 degrees, 15 degrees, 30 degrees and 55 degrees, whilst recording SV and CO every 10-sec. Baseline and percentage changes with tilting were calculated. A simulation of the tilt response was constructed, and from this residuals (observed-predicted) and prediction errors ((observed-predicted)/predicted) x 100% were calculated at 10-sec intervals. Trend analysis was performed by multiple analysis of the variance of serial measurements and graphically assessing changes in serial SV prediction errors, using Cusums. Results are presented as mean (range or SD). RESULTS: Baseline values for RCM-SV were 76 (35-94) ml and for CO 4.7 (2.8-6.1) litre x min(-1). For BoMed-SV they were 113 (90-164) ml and for CO 7.2 (5.5-11.9) litre x min(-1). Head-up tilting to 55 degrees resulted in a 32 (12)% decrease in RCM-SV and a 21 (11)% decrease in BoMed-SV (p < 0.01). Prediction errors for RCM-SV were (6.5 (4.9)%) and for BoMed-SV (6.8 (5.2)%) (p = 0.048). Cusum analysis showed that in 84% of tests, impedance measurements remained within +/- 10% of the initial calibration. There was no difference between devices (chi2 = 0.92). CONCLUSIONS: Simulation of a physiological response, such as that to head-up tilting, and using a trend analysis based on prediction errors and Cusum, is a useful technique. The trending abilities of the RCM and BoMed were similar.

Relationship between obesity and cardiovascular risk factors in elderly Chinese subjects.

OBJECTIVE: To investigate the relative effects of degree and distribution of body fat with several cardiovascular disease (CVD) risk factors in elderly Chinese subjects. METHODS: One hundred and thirty-five elderly Chinese individuals (age range, 60-65 y) without any history of significant renal, hepatic or cardiac disease were recruited. Seated blood pressure, anthropometric and fasting plasma biochemical parameters were measured. Student's t-test was used to compare the differences in biochemical and anthropometric markers between cohorts. RESULTS: Males were heavier (64.6 +/- 8.6, 57.2 +/- 8.2kg, P < 0.001), taller (1.65 +/- 0.06, 1.51 +/- 0.05 m, P < 0.001) and their greater body fat was predominantly deposited centrally (Waist-to- hip ratio, 0.91 +/- 0.06, 0.88 +/- 0.07, P < 0.05). Females were more generally obese with increased body mass index (BMI, 23.8 +/- 4.6, 25.0 +/- 3.5 kg/m2, P < 0.05) and percentage body fat [26.3% (24.5%-28.1%) vs 37.2% (36.0%-38.9%), P < 0.001] than the males. However, despite an 11% higher proportion of body fat in females, no significant differences were identified in blood pressure, lipid profile, indices of insulin resistance or albumin-to-creatinine ratios. CONCLUSION: It is likely that central adiposity contributes disproportionately to these metabolic disorders in males even though they are much leaner than elderly Chinese females.

Management of nephropathy in patients with type 2 diabetes.

PURPOSE: To review evidence-based management of nephropathy in patients with type 2 diabetes. DATA SOURCES: A literature search (MEDLINE 1966 to 2000) was performed using the key word "diabetic nephropathy". Relevant book chapters were also reviewed. STUDY SELECTION: Well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy were selected. DATA EXTRACTION: Data and conclusions from the selected articles that provide solid evidence to the optimal management of diabetic nephropathy were extracted and interpreted in light of our clinical research experience with many thousands of Hong Kong Chinese patients. RESULTS: Hypertension, long diabetes duration, poor glycaemic control and central obesity are the most important risk factors. Microalbuminuria is a practical marker to predict overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycaemic control is the mainstay of treatment but effective antihypertensive therapy is also key to delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists have important renoprotective actions independent of their blood pressure lowering actions. CONCLUSIONS: Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Monitoring renal function and screening for microalbuminuria will allow the identification of patients with nephropathy at a very early stage for intervention. Tight glycaemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.

The insulin resistance syndrome: mechanisms of clustering of cardiovascular risk.

For more than a decade, insulin resistance has been proposed as the key linking factor for the metabolic syndrome disease cluster of glucose intolerance, hypertension, dyslipidemia, obesity, and cardiovascular disease. Although most of the epidemiological, experimental, and clinical evidence still support the role of insulin resistance as an important component of this multifaceted syndrome, there is evidence amassing that a neurohormonal mechanism, including an endocrine role for adipocytes, probably plays a more fundamental role. This is supported by the strong associations between obesity, especially central adiposity, and all components of the metabolic syndrome, in contrast to the inconsistent relationships between blood pressure and markers of insulin resistance. However, much of the effect of visceral fat on cardiovascular risk factors is mediated through the metabolic actions of free fatty acids (FFA) on insulin resistance, thus resolving any obesity versus insulin resistance controversy. In addition to the roles of obesity and FFA in the development of insulin resistance syndrome, the high prevalence rates of this disease cluster among subjects from low socioeconomic groups as well as from developing countries have led to alternative hypotheses to better our understanding of the contributory roles of socioeconomic, in utero, and genetic factors in this syndrome. More recently, the pathogenetic roles of iron overload and liver dysfunction have also been re-examined. In this article, the various hypotheses which have been put forward to explain the diverse clinical manifestations of the metabolic or insulin resistance syndrome are summarized and put into perspective. While there is clinical and experimental evidence to support many of these independent pathways, alternative statistical methods such as factor analysis or structural equation modeling may be needed to unravel the complex nature of these interacting pathways. Finally, these hypotheses, if proven, will add new dimensions to our current strategies and emphasize the need to focus on behavioral and socioeconomic interventions in addition to the use of pharmacological therapy in our attempt to control this epidemic disease of modern societies.