James I. Cleeman

Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement

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 …

Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.

A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.

Definition of Metabolic Syndrome Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition

The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. The cardiovascular community has responded with heightened awareness and interest. ATP III criteria for metabolic syndrome differ somewhat from those of other organizations. Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome. The scientific evidence related to definition was reviewed and considered from several perspectives: (1) major clinical outcomes, (2) metabolic components, (3) pathogenesis, (4) clinical criteria for diagnosis, (5) risk for clinical outcomes, and (6) therapeutic interventions. ATP III viewed CVD as the primary clinical outcome of metabolic syndrome. Most individuals who develop CVD have multiple risk factors. In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X , and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome ). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors. Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes. When diabetes becomes clinically apparent, CVD risk rises sharply. Beyond CVD and type 2 diabetes, individuals with metabolic syndrome seemingly are susceptible to other conditions, notably polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some …

Diagnosis and Management of the Metabolic Syndrome An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement: Executive Summary

This Executive Summary is a synopsis of the full scientific statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI), which is intended to provide up to date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults. The metabolic syndrome has received increased attention in the past few years. It consists of multiple, interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD). This constellation of metabolic risk factors is strongly associated with type 2 diabetes mellitus or the risk for this condition. The metabolic risk factors consist of atherogenic dyslipidemia (elevated triglycerides and apolipoprotein B, small LDL particles, and low HDL cholesterol [HDL-C] concentrations), elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state. At present, it is not clear whether the metabolic syndrome has a single cause, and it appears that it can be precipitated by multiple underlying risk factors. The most important of these underlying risk factors are abdominal obesity and insulin resistance. Other associated conditions include physical inactivity, aging, hormonal imbalance, and genetic or ethnic predisposition. Prospective population studies show that the metabolic syndrome confers an &2-fold increase in relative risk for ASCVD events, and in individuals without established type 2 diabetes mellitus, an &5-fold increase in risk for developing diabetes as compared with people without the syndrome. This finding implies that the metabolic syndrome imparts a relatively high long-term risk for both ASCVD and diabetes. In the absence of diabetes, the absolute short-term (10-year) risk for major coronary heart disease (CHD) events is not necessarily high. In the Framingham Heart Study data, the 10-year risk for CHD depends on other risk factors in addition to the metabolic syndrome components contained in Framingham scoring …

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

It is interesting to look through the citation records of classic papers such as this – Bulbring & Lin (1958). It serves as a whos who in serotonin research and catalogues the development of our understanding of the role that 5-HT plays in sensory signalling from the gut lumen. Bulbring had already shown in early publications that the peristaltic reflex was entirely mediated by neural mechanisms within the bowel wall since degenerative section of the extrinsic innervation had no effect on reflex activity (Bulbring et al. 1958). They had also demonstrated that the peristaltic reflex could be triggered by distension, but required a sensory mechanism within the mucosa since it was lost after removal of the mucous membrane or following topical application of local anaesthetic. It was also evident that there was a rich source of 5-HT in the gastrointestinal tract and that this was mainly within the mucosal epithelium (Feldberg & Toh, 1953). However, there was also something of a dilemma. Carcinoid syndrome, in which there is massive outpouring of 5-HT from mucosal enterochromaffin cells, is characterized by increased intestinal activity and diarrhoea. In contrast, when 5-HT was applied to isolated intestinal segments in an organ bath it inhibited or abolished the peristaltic reflex (Kosterlitz & Robinson, 1957). Bulbring and Lin therefore set out to ask the beautifully simple question – what happens if 5-HT is applied not to the serosa but to the mucosa? Their hypothesis was that this would mimic release of endogenous 5-HT which in turn would activate receptors associated with mucosal sensory mechanisms. This classic paper describes the methodological developments that were necessary to record the propulsion of luminal contents by pressure-evoked peristalis in the guinea-pig ileum (and rabbit jejunum) during application of 5-HT to the lumen, and gives a detailed account of experiments designed to unravel the role of 5-HT in sensory signalling. First, a word or two about the available methodology. Reading again about kymographs and ‘home-made’ piston and float recorders to monitor pressure and volume contrasts with modern descriptions of solid-state electronics, digital devices and computer analysis. Limited pharmacological tools reflect the lack of appreciation at the time of the range of 5-HT receptor subtypes that are now known to be expressed in the gut mucosa and which influence sensory signalling. Assay for endogenous 5-HT was based on strips of rat stomach, uterus and colon rather than HPLC or amperometry. The paper is also very descriptive so that the reader can get a real feel for the whole study design, problems that were encountered and overcome, variability in responses and theres not a P value in sight. Yet, with cleverly designed protocols and enormous insight Bulbring and Lin established a concept for control that still holds 50 years later. Their major findings can be summarized as follows. In the guinea-pig ileum peristalsis was triggered initially by a pressure rise of just 1–1.5 cmH2O, rising to about 2 cmH2O after an hour or so. Adding 5-HT to the lumen dose-dependently decreased threshold with a threshold concentration around 1 nm. Application of 5-HT to the bath invariably caused inhibition of peristalsis, even when this was already stimulated by intraluminal 5-HT. Removing the mucosa from the loop of intestine or luminal application of cocaine or procaine abolished the peristaltic reflex and under these conditions luminal 5-HT had no effect. LSD and 2-bromo-d-LSD were used as 5-HT antagonists. Applied to the lumen they blocked the effect of co-administered 5-HT. However, when applied alone the antagonist raised the peristaltic threshold suggesting that it prevented the action of locally released 5-HT. However, peristalsis was not abolished indicating that 5-HT release is not an essential prerequisite for activation of the peristaltic reflex but is necessary to set the threshold. 5-HT overflow into the lumen increased in response to distension, an observation consistent with pressure-evoked release contributing to peristalsis. The increase was proportional to the degree of distension but declined rapidly over time. Again peristalsis was still evident even when 5-HT levels had fallen to very low levels and is therefore not essential for reflex activation to occur. The amount of 5-HT released and the decline over time could be pharma-cologically manipulated. Inhibiting 5-HT breakdown with a luminal agent to inhibit amine oxidase (1 isonicotinyl-2-isopropylhydrazine) slowed the decline in 5-HT output over time. Addition of the 5-HT precursor, 5-HTP, increased the release of 5-HT and augmented peristalsis. Procaine, which abolished peristalsis, did not prevent 5-HT release in response to distension. Bath applied hexamethonium also abolished the peristaltic reflex but, again, 5-HT release into the lumen was preserved. In contrast luminal acetylcholine (at low concentrations) stimulated peristalsis. Finally, with current interest in the role of 5-HT receptor subtypes in mucosal signalling, it is important to see that phenyldiguanide, which is now known to be a 5-HT3 receptor agonist, also stimulated peristalis when applied to the lumen. These observations are interesting in light of subsequent studies that place Enterochromaffin cells in a pivotal role in sensory signalling both for enteric reflexes and in extrinsic afferent activation. Many studies since have demonstrated that 5-HT receptor blockade can reduce or prevent reflex activation by mechanical stimulation of the mucosa or following application of chemicals to the mucosal epithelium, particularly bacterial toxins (Gershon, 1999). 5-HT receptors are present on the terminals of both enteric and extrinsic sensory neurones and convey information related to the luminal mechanical and chemical environment to enteric reflex circuits and to reflex centres in the brainstem (Hillsley & Grundy, 1998; Hillsley et al. 1998; Bertrand et al. 2000). Such observations have enormous clinical relevance. The treatment of nausea and vomiting triggered by cancer chemo- and radiotherapy has been revolutionized by the discovery that the underlying mechanism involves EC cell activation and 5-HT acting on vagal mucosal afferents (Costall & Naylor, 2004). 5-HT ligands have also been shown to have clinical efficacy in treating patients with constipation predominant and diarrhoea predominant irritable bowel syndrome (IBS) (Camilleri et al. 2002). There is growing evidence that bioavailability of 5-HT is altered in some patients with IBS, particularly those whose symptom onset is related to an acute inflammatory insult. EC cell numbers are increased and the transport mechanisms that take up 5-HT following release are reported to be blunted although this is controversial (Dunlop et al. 2005). Bulbring and Lins observations on the consequence of altering 5-HT metabolism are particularly relevant in this context. Current interest in altered 5-HT bioavailability in visceral hypersensitivity following changes in the serotonin transporter can also be traced back to their observations on the effects of increasing precursor availability and decreasing breakdown. It is also now clear that there is an elaborate arrangement of receptors and ion channels on EC cells that regulate 5-HT release. 5-HT release is modulated by a variety of neuromodulators acting on adrenoreceptors, nicotinic and muscarinic cholinoreceptors and 5-HT3 receptors (Racke et al. 1996). Bulbring and Lins observations with luminal acetylcholine and phenyldiguanide, which mimicked the effect of luminal 5-HT, may have arisen because of a common action on endogenous 5-HT release. There therefore exists a bidirectional communication between EC cells and sensory mechanisms on the one hand and enteric reflexes influencing EC cell function on the other. The work coming from Edith Bulbrings laboratory in the late 1950s was the foundation for this modern day concept.

Clinical Management of Metabolic Syndrome Report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on Scientific Issues Related to Management

The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. Subsequently, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the American Heart Association (AHA), convened a conference to examine scientific issues related to definition of the metabolic syndrome.2 The present report summarizes a second conference devoted to clinical management of the metabolic syndrome, which was sponsored by the AHA in partnership with the NHLBI and cosponsored by the American Diabetes Association (ADA). This latter conference considered the following issues: (1) pathogenesis and presentation of the metabolic syndrome, (2) management of underlying risk factors, (3) management of metabolic risk factors, and (4) unresolved issues and research challenges. The conference on definition2 confirmed CVD as a major clinical outcome of metabolic syndrome and identified 6 major components of the syndrome: abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance ± glucose intolerance, a proinflammatory state, and a prothrombotic state. The follow-up conference on management was structured around therapies for these components. Clinical recognition of the metabolic syndrome is generally based on finding several well-recognized signs in clinical practice: abdominal obesity, elevated triglycerides, reduced HDL cholesterol, raised blood pressure, and elevated plasma glucose. In addition, research shows that other components not routinely measured commonly aggregate with the major components: elevated apolipoprotein B, small LDL particles, insulin resistance and hyperinsulinemia, impaired glucose tolerance (IGT), elevated C-reactive protein (CRP), and variation in coagulation factors (eg, plasminogen activator inhibitor [PAI]-1 and fibrinogen). The conference on definition2 also emphasized that risk for type 2 diabetes is higher in persons with metabolic syndrome and that diabetes is a major risk factor for CVD. It also examined various criteria for …

Cardiovascular Risk Assessment Based on US Cohort Studies Findings From a National Heart, Lung, and Blood Institute Workshop

This report was derived from a workshop on cardiovascular risk assessment sponsored by the National Heart, Lung, and Blood Institute, which addressed whether risk equations developed in the Framingham Heart Study (FHS) for predicting new-onset coronary heart disease (CHD) apply to diverse population groups. Preparation for the workshop included a reanalysis and comparison of prospective studies in several different populations in which risk factors were related to cardiovascular outcomes. Some studies included fatal and nonfatal CHD end points, whereas others contained only CHD mortality. Extensive collaboration provided as much uniformity as possible with respect to both risk factors and CHD end points. The FHS has led in defining the quantitative impact of risk factors.1 Many potential risk factors were measured and related to cardiovascular outcomes. Several risk factors proved to be strong, largely independent predictors of cardiovascular disease (CVD). These factors—advancing age, cigarette smoking, blood pressure (particularly systolic), cholesterol in total serum and HDL, and diabetes—served as the basis for the development of risk prediction equations.1 If FHS risk estimates are to be widely used, they must apply widely in the US population. To document their transportability, they must be compared with prospective studies in other populations. Although the FHS is the longest running prospective study, there are other major studies. The cardiovascular end points of these other studies have varied. Some include cardiovascular morbidity and mortality; others have only cardiovascular mortality. Among the end points, CHD is the most extensively reported; for this reason, CHD was the primary focus of the workshop. ### Multivariate Relative Risk Comparisons In preparation for the workshop, multivariate regression coefficients for each risk factor were compared in different populations with those of the FHS. Adjusted relative risk estimates make it possible to determine whether each independent risk factor confers a similar or different relative risk among different …

National cholesterol education program keeps a priority on lifestyle modification to decrease cardiovascular disease risk

&NA; The National Cholesterol Education Programs updated third Adult Treatment Panel report on clinical guidelines for cholesterol testing and management adds to the base of knowledge provided by two previous Adult Treatment Panel reports. Similar to the other reports, it has distinctive features and goals that are in accord with the most currently available clinical trial evidence. The major new feature of the third report is a focus on primary prevention of coronary heart disease in persons with multiple coronary heart disease risk factors. The guidelines provide the rationale for intensive cholesterol‐lowering therapy in clinical management, and they provide detailed information to help inform clinical judgment for implementation of both medical nutrition management (therapeutic lifestyle changes) and drug therapy for treatment of high blood cholesterol.

Reducing high blood cholesterol levels: Recommendations from the national cholesterol education program

Modification of risk factors is the major clinical and public health approach to the prevention of coronary heart disease (CHD). To coordinate national efforts to reduce the three major modifiable CHD risk factors of high blood pressure, cigarette smoking, and high blood cholesterol, the National Heart, Lung, and Blood Institute (NHLBI) has established three educational programs: the National High Blood Pressure Education Program, the NHLBI Smoking Education Program, and the National Cholesterol Education Program. This article focuses on the most recent of these efforts, the National Cholesterol Education Program (NCEP). A perspective of the concepts and basis of this effort is afforded by a brief description of the National Cholesterol Education Programs predecessor, the National High Blood Pressure Education Program (NHBPEP).