CardioMetabolic Health Alliance: Metabolic Syndrome Model
CardioMetabolic Health Alliance: Metabolic Syndrome Model
MetS recognizes a group of risk factors underlying cardiovascular and metabolic disease. The most accepted clinical definition, established by the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) in 2001, recognizes multiple components of the syndrome related to atherosclerotic cardiovascular disease (ASCVD) risk: abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance with or without glucose intolerance, proinflammatory state, and prothrombotic state. The criteria for clinical diagnosis of MetS are 3 or more of the following: 1) waist circumference >102 cm (40 in) in men and 88 cm (35 in) in women; 2) triglycerides ≥150 mg/dl; 3) high-density lipoprotein cholesterol (HDL-C) <40 mg/dl in men and <50 mg/dl in women; 4) blood pressure ≥130/85 mm Hg; and 5) fasting glucose ≥100 mg/dl. In 2005, the NCEP-ATP III criteria were modified to suggest lower waist circumference cutpoints for Asian Americans (≥90 cm [35 inches] in men and ≥80 cm [31 inches] in women). However, these criteria do not fully encompass the pathophysiological complexity of the syndrome, recognize predisposition to different types of end-organ damage, or account for health disparities according to race, sex, or socioeconomic status, in screening for or treating the syndrome.
MetS is typically under-recognized in the clinical setting, even just on the basis of the 5 standard criteria. Additional elements of MetS include high apolipoprotein B, small low-density lipoprotein (LDL) particle size, endothelial dysfunction, insulin resistance, and prothrombotic and proinflammatory states. Not only are these less widely appreciated as components of MetS, but they are also not typically measured in a clinical setting. MetS consists of elements that do not aggregate by chance alone and are causally inter-related, and each element contributes independently to an increased risk for ASCVD. Factor analysis in epidemiological studies in different populations, including adolescents and ethnic minorities, demonstrates clustering of risk in the domains of adiposity and/or dyslipidemia, hyperglycemia or insulin resistance, and hypertension that explain 37% to 70% of variation and vary by sex and race. For example, Malay women with MetS had different factor patterns with greater importance of hypertension, insulin resistance, and triglycerides when compared with other South Asian women. These findings highlight the racial phenotypic variability of MetS that is not well captured by standard MetS paradigms.
Additionally, ASCVD risk rises exponentially as the number of MetS elements increases. In the Hoorn study in the Netherlands, the risk of cardiovascular outcomes rose rapidly with an increasing number of MetS components, becoming statistically significant at ≥3 factors for men and ≥2 factors for women. Other studies have demonstrated that MetS compounds the risk for ASCVD when other known risk factors, such as T2D, are present. A meta-analysis, including 87 studies with 951,083 patients, demonstrated that MetS was associated with a >2-fold increased risk for ASCVD and cardiovascular mortality. MetS is present in ~50% of patients with diagnosed vascular disease and may be even more prevalent among women with ASCVD. In the Framingham Offspring Study, both MetS and T2D increased the risk of stroke by approximately 2-fold, and those patients with both had an even higher risk. ASCVD risk is higher with MetS in the absence of T2D compared with T2D without MetS (13.9% vs. 7.5%, respectively).
The prevalence of MetS increases dramatically with increasing obesity. In men in the NHANES (National Health and Nutrition Examination Survey) from 2003 to 2006, MetS was present in 6.8% of normal weight, 29.8 % of overweight, and 65% of obese individuals. Similarly, among women, 9.3% of normal weight, 33.1% of overweight, and 56.1% of obese individuals had MetS. Susceptibility to MetS transcends obesity, however, as there are obese individuals without MetS and nonobese individuals with MetS. Several factors modulate the prevalence of MetS in the presence of obesity, including lifestyle factors such as poor nutritional quality and lack of physical activity. Age, race, and sex also contribute to metabolic susceptibility, in part mediated by differences in adipose tissue distribution and adipocyte size and function. For example, South Asians have higher body fat content, waist to hip ratio, visceral fat to subcutaneous fat ratio, and adipocyte area than Caucasians matched for age, sex, and body mass index (BMI). Similarly, Filipina women may have higher waist circumference and truncal fat and 3- to 4-fold higher rates of type 2 diabetes (T2D) and MetS compared with Caucasian women, controlling for other factors.
In the Dallas Heart Study, total body fat correlated with multiple metabolic risk factors, including insulin resistance. Excess truncal fat further increased risk after adjusting for total body fat. Conversely, lower body subcutaneous fat was protective, and waist circumference appeared to be a better predictor of total body fat than BMI. Visceral adipose tissue (VAT) appears to be associated with dyslipidemia and atherosclerosis, regardless of sex or race. Finally, adipocyte size and lack of hyperplasia is associated with adipose tissue dysfunction, inflammatory markers, and insulin resistance. Given these findings, using a combination of BMI and waist circumference in MetS risk assessment may prove better than either measure alone. There may also need to be thresholds for waist circumference and BMI that differ by race.
The challenge presented to the TT was 3-fold. First, the current definition of MetS identifies a population at increased ASCVD risk, but does not accurately assess that risk, nor does it account for susceptibility for a given degree of adiposity, as noted earlier. Second, there is no targeted comprehensive care approach to address the needs of MetS patients. Third, assuming there was such an approach, there is no system to implement risk reduction and disease prevention. In the sections that follow, each of these issues is addressed, culminating in the formulation of affirmed concepts, emergent concepts, and key findings relevant to MetS care.
Introduction
MetS recognizes a group of risk factors underlying cardiovascular and metabolic disease. The most accepted clinical definition, established by the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) in 2001, recognizes multiple components of the syndrome related to atherosclerotic cardiovascular disease (ASCVD) risk: abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance with or without glucose intolerance, proinflammatory state, and prothrombotic state. The criteria for clinical diagnosis of MetS are 3 or more of the following: 1) waist circumference >102 cm (40 in) in men and 88 cm (35 in) in women; 2) triglycerides ≥150 mg/dl; 3) high-density lipoprotein cholesterol (HDL-C) <40 mg/dl in men and <50 mg/dl in women; 4) blood pressure ≥130/85 mm Hg; and 5) fasting glucose ≥100 mg/dl. In 2005, the NCEP-ATP III criteria were modified to suggest lower waist circumference cutpoints for Asian Americans (≥90 cm [35 inches] in men and ≥80 cm [31 inches] in women). However, these criteria do not fully encompass the pathophysiological complexity of the syndrome, recognize predisposition to different types of end-organ damage, or account for health disparities according to race, sex, or socioeconomic status, in screening for or treating the syndrome.
MetS is typically under-recognized in the clinical setting, even just on the basis of the 5 standard criteria. Additional elements of MetS include high apolipoprotein B, small low-density lipoprotein (LDL) particle size, endothelial dysfunction, insulin resistance, and prothrombotic and proinflammatory states. Not only are these less widely appreciated as components of MetS, but they are also not typically measured in a clinical setting. MetS consists of elements that do not aggregate by chance alone and are causally inter-related, and each element contributes independently to an increased risk for ASCVD. Factor analysis in epidemiological studies in different populations, including adolescents and ethnic minorities, demonstrates clustering of risk in the domains of adiposity and/or dyslipidemia, hyperglycemia or insulin resistance, and hypertension that explain 37% to 70% of variation and vary by sex and race. For example, Malay women with MetS had different factor patterns with greater importance of hypertension, insulin resistance, and triglycerides when compared with other South Asian women. These findings highlight the racial phenotypic variability of MetS that is not well captured by standard MetS paradigms.
Additionally, ASCVD risk rises exponentially as the number of MetS elements increases. In the Hoorn study in the Netherlands, the risk of cardiovascular outcomes rose rapidly with an increasing number of MetS components, becoming statistically significant at ≥3 factors for men and ≥2 factors for women. Other studies have demonstrated that MetS compounds the risk for ASCVD when other known risk factors, such as T2D, are present. A meta-analysis, including 87 studies with 951,083 patients, demonstrated that MetS was associated with a >2-fold increased risk for ASCVD and cardiovascular mortality. MetS is present in ~50% of patients with diagnosed vascular disease and may be even more prevalent among women with ASCVD. In the Framingham Offspring Study, both MetS and T2D increased the risk of stroke by approximately 2-fold, and those patients with both had an even higher risk. ASCVD risk is higher with MetS in the absence of T2D compared with T2D without MetS (13.9% vs. 7.5%, respectively).
The prevalence of MetS increases dramatically with increasing obesity. In men in the NHANES (National Health and Nutrition Examination Survey) from 2003 to 2006, MetS was present in 6.8% of normal weight, 29.8 % of overweight, and 65% of obese individuals. Similarly, among women, 9.3% of normal weight, 33.1% of overweight, and 56.1% of obese individuals had MetS. Susceptibility to MetS transcends obesity, however, as there are obese individuals without MetS and nonobese individuals with MetS. Several factors modulate the prevalence of MetS in the presence of obesity, including lifestyle factors such as poor nutritional quality and lack of physical activity. Age, race, and sex also contribute to metabolic susceptibility, in part mediated by differences in adipose tissue distribution and adipocyte size and function. For example, South Asians have higher body fat content, waist to hip ratio, visceral fat to subcutaneous fat ratio, and adipocyte area than Caucasians matched for age, sex, and body mass index (BMI). Similarly, Filipina women may have higher waist circumference and truncal fat and 3- to 4-fold higher rates of type 2 diabetes (T2D) and MetS compared with Caucasian women, controlling for other factors.
In the Dallas Heart Study, total body fat correlated with multiple metabolic risk factors, including insulin resistance. Excess truncal fat further increased risk after adjusting for total body fat. Conversely, lower body subcutaneous fat was protective, and waist circumference appeared to be a better predictor of total body fat than BMI. Visceral adipose tissue (VAT) appears to be associated with dyslipidemia and atherosclerosis, regardless of sex or race. Finally, adipocyte size and lack of hyperplasia is associated with adipose tissue dysfunction, inflammatory markers, and insulin resistance. Given these findings, using a combination of BMI and waist circumference in MetS risk assessment may prove better than either measure alone. There may also need to be thresholds for waist circumference and BMI that differ by race.
The challenge presented to the TT was 3-fold. First, the current definition of MetS identifies a population at increased ASCVD risk, but does not accurately assess that risk, nor does it account for susceptibility for a given degree of adiposity, as noted earlier. Second, there is no targeted comprehensive care approach to address the needs of MetS patients. Third, assuming there was such an approach, there is no system to implement risk reduction and disease prevention. In the sections that follow, each of these issues is addressed, culminating in the formulation of affirmed concepts, emergent concepts, and key findings relevant to MetS care.
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