Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia

A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors, was able to remove LDL cholesterol from plasma at a nearly normal rate. We conclude that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation. These data underscore the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings. (N Engl J Med 1984; 311: 1658–64.). © 1984, Massachusetts Medical Society. All rights reserved

primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk an endocrine society clinical practice guideline

Objective: The objective was to develop clinical practice guidelines for the primary prevention of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) in patients at metabolic risk. Conclusions: Healthcare providers should incorporate into their practice concrete measures to reduce the risk of developing CVD and T2DM. These include the regular screening and identification of patients at metabolic risk (at higher risk for both CVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose. All patients identified as having metabolic risk should undergo 10-yr global risk assessment for either CVD or coronary heart disease. This scoring will determine the targets of therapy for reduction of apolipoprotein B-containing lipoproteins. Careful attention should be given to the treatment of elevated blood pressure to the targets outlined in this guideline. The prothrombotic state associated with metabolic risk should be treated with lifestyle modification measures and in appropriate individuals with low-dose aspirin prophylaxis. Patients with prediabetes (impaired glucose tolerance or impaired fasting glucose) should be screened at 1- to 2-yr intervals for the development of diabetes with either measurement of fasting plasma glucose or a 2-h oral glucose tolerance test. For the prevention of CVD and T2DM, we recommend that priority be given to lifestyle management.Thisincludesantiatherogenicdietarymodification,aprogramofincreasedphysicalactivity, andweightreduction.Effortstopromotelifestylemodificationshouldbeconsideredanimportant component of the medical management of patients to reduce the risk of both CVD and T2DM. (J Clin Endocrinol Metab 93: 3671–3689, 2008

Improving coronary heart disease risk assessment in asymptomatic people: Role of traditional risk factors and noninvasive cardiovascular tests

At least 25% of coronary patients have sudden death or nonfatal myocardial infarction without prior symptoms.1 Therefore, the search for coronary patients with subclinical disease who could potentially benefit from intensive primary prevention efforts is critically important. The American Heart Association’s (AHA) Prevention V Conference, “Beyond Secondary Prevention: Identifying the High Risk Patient for Primary Prevention,” addressed ways to identify more patients who are asymptomatic and clinically free of coronary heart disease (CHD) but at sufficiently high risk for a future coronary event to justify more intensive risk reduction efforts.2 In this report, we amplify on key findings and recommendations of the AHA Prevention V conference, highlight new research since the conference, and propose an approach to the use of office-based testing and additional noninvasive procedures in selected patients to better define their coronary event risk. The recommendations are concordant with the recently released approach to risk assessment and management from the third report of the Adult Treatment Panel of the National Cholesterol Education Program (ATP-III).

Prevention Conference V: Beyond secondary prevention: Identifying the high-risk patient for primary prevention: Executive summary

"This conference, “Beyond Secondary Prevention: Identifying the High-Risk Patient for Primary Prevention,” which was the fifth in a series of prevention conferences sponsored by the American Heart Association (AHA), was held October 26–28, 1998, in San Francisco, Calif. The need for this conference was precipitated by the remarkable advances in medical therapies for the prevention of coronary heart disease (CHD). The AHA has already set forth guidelines for aggressive medical therapy in patients with established CHD (secondary prevention). The major issue under consideration at this conference was the development of strategies to identify high-risk patients without established CHD who are candidates for aggressive medical therapies for primary prevention. Therefore, a central theme for the conference was the emphasis on establishing a prognosis for high-risk patients without clinical evidence of CHD. Three writing groups were established to report on the following areas: (1) medical office assessment, (2) tests for silent and inducible ischemia, and (3) noninvasive tests of atherosclerotic burden. Each working group reviewed research on existing risk-assessment strategies relevant to the prediction of risk in patients without clinical evidence of CHD. The key findings of each working group are presented in this Executive Summary of the conference. The full conference report with references is available online at http://circ.ahajournals.org/ in the January 4, 2000, issue of Circulation. The recommended strategies will assist in expanding preventive therapies, including lipid lowering, blood pressure control, smoking cessation, diet, and exercise, to patients at high risk for developing CHD. The following briefly summarizes the major conclusions of the conference.

Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology

The past decade has witnessed major strides in the prevention of coronary heart disease (CHD) through modification of its causes. The most dramatic advance has been the demonstration that aggressive medical therapy will substantially reduce the likelihood of recurrent major coronary syndromes in patients with established CHD (secondary prevention). The American Heart Association (AHA) and the American College of Cardiology (ACC) have published joint recommendations for medical intervention in patients with CHD and other forms of atherosclerotic disease.1 A similar potential exists for risk reduction in patients without established CHD (primary prevention). However, the risk status of persons without CHD varies greatly, and this variability mandates a range in the intensity of interventions. Effective primary prevention thus requires an assessment of risk to categorize patients for selection of appropriate interventions. The present statement is being published jointly by the AHA and ACC to outline current issues and approaches to global risk assessment for primary prevention. The approaches described in this statement can be used for guidance at several levels of primary prevention; however, the statement does not attempt to specifically link risk assessment to treatment guidelines for particular risk factors. Nonetheless, it provides critical background information that can be used in the development of new treatment guidelines

Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology

The past decade has witnessed major strides in the prevention of coronary heart disease (CHD) through modification of its causes. The most dramatic advance has been the demonstration that aggressive medical therapy will substantially reduce the likelihood of recurrent major coronary syndromes in patients with established CHD (secondary prevention). The American Heart Association (AHA) and the American College of Cardiology (ACC) have published joint recommendations for medical intervention in patients with CHD and other forms of atherosclerotic disease 1. A similar potential exists for risk reduction in patients without established CHD (primary prevention). However, the risk status of persons without CHD varies greatly, and this variability mandates a range in the intensity of interventions. Effective primary prevention thus requires an assessment of risk to categorize patients for selection of appropriate interventions. The present statement is being published jointly by the AHA and ACC to outline current issues and approaches to global risk assessment for primary prevention. The approaches described in this statement can be used for guidance at several levels of primary prevention; however, the statement does not attempt to specifically link risk assessment to treatment guidelines for particular risk factors. Nonetheless, it provides critical background information that can be used in the development of new treatment guidelines

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 a clinical diagnosis of the metabolic syndrome. The diagnostic scheme developed by ATP III is shown in the Table. Clinical criteria proposed by the World Health Organization3 and American Association of Clinical Endocrinologists4 also were reviewed. These latter criteria overlap with those of ATP III but differ by requiring direct evidence of insulin resistance for diagnosis. Both the World Health Organization and the American Association of Clinical Endocrinologists recommend an oral glucose tolerance test (OGTT) in patients without an elevated fasting glucose. In other words, in the absence of impaired fasting glucose (IFG), IGT detected by OGTT is considered as one metabolic risk factor defining the metabolic syndrome. ATP III does not recommend OGTT in such persons, even through IGT is a high-risk condition for type 2 diabetes (independent of IFG) and correlates with increased risk for CVD. ATP III, however, held that the information gained by OGTT does not outweigh its costs and inconvenience in routine practice. The present conference on management moved from the issue of definition of the metabolic syndrome to the wide issues of clinical management.