Showing papers by "Scott M. Grundy published in 2006"

Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.

Abstract: The metabolic syndrome has received increased attention in the past few years. This statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) is intended to provide up-to-date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults. The metabolic syndrome is a constellation of interrelated risk factors of metabolic origin— metabolic risk factors —that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD).1 Patients with the metabolic syndrome also are at increased risk for developing type 2 diabetes mellitus. Another set of conditions, the underlying risk factors , give rise to the metabolic risk factors. In the past few years, several expert groups have attempted to set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general they include a combination of both underlying and metabolic risk factors. The most widely recognized of the metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a pro-inflammatory state as well. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities including elevated serum triglyceride and apolipoprotein B (apoB), increased small LDL particles, and a reduced level of HDL cholesterol (HDL-C). The metabolic syndrome is often referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of cause, the syndrome identifies individuals at an elevated risk for ASCVD. The magnitude of the increased risk can vary according to which components of the syndrome are …

AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2006 Update Endorsed by the National Heart, Lung, and Blood Institute

Abstract: Since the 2001 update of the American Heart Association (AHA)/American College of Cardiology (ACC) consensus statement on secondary prevention,1 important evidence from clinical trials has emerged that further supports and broadens the merits of aggressive risk-reduction therapies for patients with established coronary and other atherosclerotic vascular disease, including peripheral arterial disease, atherosclerotic aortic disease, and carotid artery disease. This growing body of evidence confirms that aggressive comprehensive risk factor management improves survival, reduces recurrent events and the need for interventional procedures, and improves quality of life for these patients. Compelling evidence from recent clinical trials and revised practice guidelines provided the impetus for this update of the 2001 recommendations with evidence-based results (Table 1⇓). Classification of Recommendations and Level of Evidence are expressed in ACC/AHA format, as detailed in Tables 2 and 3⇓. Recommendations made herein are based largely on major practice guidelines from the National Institutes of Health and ACC/AHA. In many cases, these practice guidelines were supplemented by research findings published after the publication of the primary reference(s). Thus, the development of the present statement involved a process of partial adaptation of other guideline statements and reports and supplemental literature searches.2–32 (For specific search criteria, see the Appendix.) The findings from additional lipid reduction trials33–37 involving more than 50 000 patients resulted in new optional therapeutic targets, which were outlined in the 2004 update of the National Heart, Lung, and Blood Institute’s Adult Treatment Panel (ATP) III report.6 These changes defined optional lower target cholesterol levels for very high-risk coronary heart disease (CHD) patients, especially those with acute coronary syndromes, and expanded indications for drug treatment. …

Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus A Scientific Statement From the American Heart Association and the American Diabetes Association

Abstract: The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study.

Abstract: OBJECTIVE —The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS —A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 ( n = 753) or 80 ( n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS —End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58–0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48–0.98], P = 0.037) and any cardiovascular event (0.85 [0.73–1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS —Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.

Abstract: An approach to understand quantitative traits was recently proposed based on the finding that nonsynonymous (NS) sequence variants in certain genes are preferentially enriched at one extreme of the population distribution. The NS variants, although individually rare, are cumulatively frequent and influence quantitative traits, such as plasma lipoprotein levels. Here, we use the NS variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (LDLs). The ratio of plasma campesterol (a plant sterol) to lathosterol (a cholesterol precursor) was used to estimate relative cholesterol absorption in a population-based study. Nonsynonymous sequence variations in NPC1L1 were five times more common in low absorbers (n = 26 of 256) than in high absorbers (n = 5 of 256) (P < 0.001). The rare variants identified in low absorbers were found in 6% of 1,832 African-Americans and were associated with lower plasma levels of LDL cholesterol (LDL-C) (96 ± 36 mg/dl vs. 105 ± 36 mg/dl; P = 0.005). These data, together with prior findings, reveal a genetic architecture for LDL-C levels that does not conform to current models for quantitative traits and indicate that a significant fraction of genetic variance in LDL-C is due to multiple alleles with modest effects that are present at low frequencies in the population. cholesterol absorption complex trait genetic architecture mutation plant sterol

Influence of body fat content and distribution on variation in metabolic risk.

Abstract: Objectives: Several reports indicate that the body fat compartments, especially ip fat, predict metabolic risk better than total body fat. The objective of the study was to determine whether this can be confirmed and generalized throughout the population. Participants: A representative sample of 1934 Black and White women and men of the Dallas Heart Study participated in the study. Design: We measured the fat in total body, trunk, and lower body with dual-energy x-ray absorptiometry and in abdominal compartments (sc, ip, and retroperitoneal) with magnetic resonance imaging. Other measurements included body mass index (BMI), waist circumference, blood pressure, plasma lipids, glucose, insulin (including homeostasis model), and C-reactive protein. Results: In all groups, total body fat correlated positively with key metabolic risk factors, i.e. homeostasis model, triglyceride/high-density lipoprotein-cholesterol ratios, C-reactive protein, and blood pressure; however, it explained less than one third of the...

Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy

Abstract: The metabolic syndrome--a collection of factors associated with increased risk for cardiovascular disease and diabetes--is becoming increasingly common, largely as a result of the increase in the prevalence of obesity. Although it is generally agreed that first-line clinical intervention for the metabolic syndrome is lifestyle change, this is insufficient to normalize the risk factors in many patients, and so residual risk could be high enough to justify drug therapy. However, at present there are no approved drugs that can reliably reduce all of the metabolic risk factors over the long term, and so there is growing interest in therapeutic strategies that might target multiple risk factors more effectively, thereby minimizing problems with polypharmacy. This review summarizes current understanding of the nature of the metabolic syndrome, and discusses each of the risk factors of the metabolic syndrome as possible primary drug targets; potential secondary or tertiary targets are also considered.

Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease.

Abstract: To determine if non–high-density lipoprotein (HDL) cholesterol is a more useful predictor of coronary heart disease (CHD) risk than low-density lipoprotein (LDL) cholesterol and if very-low-density lipoprotein (VLDL) cholesterol is an independent predictor of CHD risk, data from the Framingham Heart Study (2,693 men, 3,101 women) were used for this analysis. All subjects were aged ≥30 years and free of CHD at baseline, and incident CHD was the end point (618 men, 372 women). Cox proportional-hazards models were used to assess the risk for CHD (relative risks and 95% confidence intervals) on the basis of the joint distribution of LDL cholesterol and non-HDL cholesterol (in milligrams per deciliter), as well as LDL cholesterol, non-HDL cholesterol, and VLDL cholesterol as continuous variables. After multivariate adjustment, within non-HDL cholesterol level, no association was found between LDL cholesterol and the risk for CHD, whereas within LDL cholesterol levels, a strong positive and graded association between non-HDL cholesterol and risk for CHD was observed. When the analysis was repeated within triglyceride levels (

Does the metabolic syndrome exist

Abstract: In recent years, several organizations have proposed that the metabolic syndrome be introduced into clinical practice as a multidimensional risk condition for both atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes (rev. in 1). This proposal generally has been well received. Recently, however, Kahn et al. (2) questioned whether evidence for the existence and characteristics of the metabolic syndrome is sufficiently developed to support its inclusion in clinical practice. Several critical issues were broached in their article. The present commentary will attempt to briefly respond to the issues raised. Five risk factors of metabolic origin (atherogenic dyslipidemia, elevated blood pressure, elevated glucose, a prothrombotic state, and a proinflammatory state) commonly cluster together (1). This aggregation is frequently observed in clinical practice, and it has been convincingly documented in prospective studies by cluster analyses (3). Risk factor clustering cannot be explained by chance occurrence alone. Thus, if the metabolic syndrome is defined as multiple risk factors that are metabolically interrelated, then the syndrome certainly exists. The commonly observed aggregation of metabolic risk factors has gone by several different names: syndrome X, insulin resistance syndrome, pre-diabetes, metabolic syndrome, dysmetabolic syndrome, plurimetabolic syndrome, cardiometabolic syndrome, dyslipidemic hypertension, hypertriglyceridemic waist, and deadly quartet (1). No single term has been universally accepted, and terminology likely will continue to be a topic of some disagreement. Kahn et al. have misgivings regarding whether the clustering of risk factors deserves the name “syndrome,” although most investigators are accepting of it. Among the various names, “metabolic syndrome” is widely used and broadly accepted in both cardiovascular and diabetes fields. It is general and does not commit to a particular pathogenesis. Consequently, it is reasonable to employ the term because of precedent and common usage. The term appears to be at least as good as any of the alternatives. For …

Role of Genetic Polymorphism Peroxisome Proliferator–Activated Receptor-γ2 Pro12Ala on Ethnic Susceptibility to Diabetes in South-Asian and Caucasian Subjects: Evidence for heterogeneity

Abstract: OBJECTIVE —To determine whether the peroxisome proliferator–activated receptor (PPAR)-γ Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS —South Asians ( n = 697) and Caucasians ( n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India ( n = 1,619), were enrolled for this study. PPAR-γ Pro12Ala was determined using restriction fragment–length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS —The Caucasian diabetic subjects had significantly lower prevalence of PPAR-γ 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-γ Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 ± 68 and 54 ± 33 μU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-γ Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS —Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-γ Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

Ethnic-Specific Criteria for the Metabolic Syndrome Evidence from China

Abstract: The metabolic syndrome is a constellation of interrelated abnormalities, including dyslipidemia, elevated blood pressure and glucose, and prothrombotic and proinflammatory states (1). Because of the growing prevalence of the metabolic syndrome, several organizations have attempted to set forth clinical criteria for its diagnosis (1–5). The most recent are those proposed by the International Diabetes Federation (IDF) definition (5) and the American Heart Association’s National Heart, Lung, and Blood Institute (1). The latter updated the National Cholesterol Education Program Adult Treatment Panel III (ATPIII) criteria (2). Both IDF and updated ATPIII criteria emphasized the importance of adiposity in the etiology of the metabolic syndrome and recommended specific thresholds for central obesity in different ethnic groups. Thresholds in the two reports were identical for Asian populations. A significant difference between the two criteria is that the IDF makes central obesity necessary for diagnosis, whereas updated ATPIII criteria did not. Whether the prerequisite of central obesity has any impact on the prevalence or the classification of the syndrome in the Chinese population is unknown. The objective of this study is to assess the prevalence of the metabolic syndrome in the Chinese population using the ethnic-specific …

Diabetes and coronary risk equivalency: what does it mean?

Abstract: The National Cholesterol Education Program Adult Treatment Panel III (ATP III) listed diabetes as a coronary heart disease (CHD) risk equivalent for setting therapeutic goals for LDL cholesterol (1). A goal for LDL cholesterol of 20%. For the majority of patients with diabetes, this LDL cholesterol goal would evoke the use of cholesterol-lowering drugs, particularly statins. Some investigators have questioned whether most or all patients with diabetes have a CHD risk equivalent and thus require cholesterol-lowering drugs (2). One approach to this issue is to examine epidemiological data relating to absolute risk for developing CHD in various populations of persons with diabetes. In the present issue of Diabetes Care , Howard et al. (3) reported the incidence of CHD in the Strong Heart Study, a cohort study of cardiovascular disease (CVD) in 13 American-Indian tribes/communities conducted in three study centers in southwestern Oklahoma, central Arizona, and North and South Dakota. The population of the Strong Heart Study has a high prevalence of type 2 diabetes and CVD associated with diabetes. The findings of this study showed wide variation in rates of CHD in patients with diabetes, depending in part on coexisting risk factors. Most individuals had 10-year risk >20%, the threshold for ATP III’s CHD risk equivalency, but only those with multiple risk factors had rates of CHD events equivalent to patients with established CHD. The authors conclude that it may be prudent to consider therapeutic goals for risk factors based on the entire risk factor profile, rather than just the presence of diabetes. Other studies likewise have found …

Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors

Abstract: Ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1) inhibits the insulin receptor. E-NPP1 mutations are associated with type 2 diabetes, and E-NPP1 expression is increased in nonobese, nondiabetic insulin-resistant subjects; E-NPP1 might therefore act as a marker for at-risk individuals and reveal new targets for prevention and treatment of diabetes and cardiovascular disease. Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its β-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described.The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.

The metabolic syndrome: a call to action.

Abstract: Metabolic syndrome, a cluster of risk factors that enhances the risk for atherosclerotic cardiovascular disease, has received increasing attention in recent years, especially as the worldwide prevalence of obesity has become better defined. Recent controversy has questioned the scientific basis for metabolic syndrome, but does not negate its value as a description of a common phenotype of patients encountered in clinical practice. Revised and refined diagnostic criteria may be useful for physicians. While more research is needed to understand the pathology of the metabolic syndrome, there is no ambiguity that physicians should treat cardiovascular risk factors in individuals with metabolic syndrome.

Metabolic syndrome and hyperglycemia: congruence and divergence.

Abstract: C t g p c w T g t The metabolic syndrome consists of a clustering of metbolic risk factors that increase the risk for coronary heart isease (CHD) and other forms of atherosclerotic cardioascular disease (CVD). These risk factors include atheroenic dyslipidemia, elevated blood pressure, elevated lasma glucose, a prothrombotic state, and a proinflammaory state. One of these risk factors, elevated fasting plasma lucose or fasting hyperglycemia, can be divided (dependng on the degree of abnormality) into impaired fasting lucose (IFG), fasting glucose 100 to 125 mg/dl, or type 2 iabetes (fasting glucose 126 mg/dl). The National Cholesterol Education Program introduced linical criteria in 2001 as a way to diagnose the metabolic yndrome in clinical practice.1 These include 3 of 5 of the ollowing components: abdominal obesity (waist circumfernce 102 cm in men and 88 cm in women), triglycerides 150 mg/dl, high-density lipoprotein (HDL) cholesterol 40 mg/dl in men and 50 mg/dl in women, elevated lood pressure (systolic 130 mm Hg and/or diastolic 85 m Hg), and elevated fasting glucose ( 110 mg/dl). A 004 update of these guidelines2 reduced the threshold for levated fasting glucose to 100 mg/dl, in accord with Amercan Diabetes Association recommendations; it also made drug reatment for any component a diagnostic criterion. Diabetes mellitus is considered a high-risk condition for HD,3,4 whereas those with IFG are often at increased risk or CHD5 and conversion to diabetes.6 In 1988, Reaven7 ypothesized that insulin resistance is a common link in the athogenesis of hyperglycemia and other cardiovascular isk factors (syndrome X). Although other additional factors e.g., obesity) appear to be involved in pathogenesis, the ommon link proposed by Reaven7 has acted as a catalyst to ring together cardiovascular and diabetes researchers. The onnection between these disciplines is strengthened beause most patients with type 2 diabetes die as a direct result f CVD and because hyperglycemia is common in patients resenting with cardiac conditions.8 Despite this overlap, here has been much ambivalence about the concept of the etabolic syndrome.9–12 Many investigators have embraced he concept of the metabolic syndrome; others, however, are ot comfortable with the concept and may view IFG and ype 2 diabetes as sufficient predictors of CVD.

Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q.

Abstract: Summary Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results. We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06). Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.

Heart, Lung, and Blood Institute Other Atherosclerotic Vascular Disease: 2006 Update: Endorsed by the National AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and

Abstract: Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/CIRCULATIONAHA.106.174516 2006;113;2363-2372 Circulation Kathryn A. Taubert Krumholz, Lori Mosca, Richard C. Pasternak, Thomas Pearson, Marc A. Pfeffer and Brass, Gregg C. Fonarow, Scott M. Grundy, Loren Hiratzka, Daniel Jones, Harlan M. Sidney C. Smith, Jr, Jerilyn Allen, Steven N. Blair, Robert O. Bonow, Lawrence M. Heart, Lung, and Blood Institute Other Atherosclerotic Vascular Disease: 2006 Update: Endorsed by the National AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and http://circ.ahajournals.org/cgi/content/full/113/19/2363 located on the World Wide Web at: The online version of this article, along with updated information and services, is

Does the Metabolic Syndrome Exist?: Response to Davidson

Abstract: In response to Davidson (1), who questions whether the metabolic syndrome conveys more risk for cardiovascular disease (CVD) than that contained in its risk components, I suggest that this debate is partly confused by ambiguity over the issues of prediction versus causation. The argument based on prediction contends that among the diagnostic components of the syndrome (elevated blood pressure, low levels of HDL cholesterol, high triglycerides, elevated glucose, and abdominal obesity), most of the predictive power is contained in blood pressure and HDL cholesterol. Therefore, in epidemiological studies, the short-term risk for CVD for the syndrome as a whole, assessed by current …