Obesity and Cardiovascular Disease

【摘要】  Obesity is becoming a global epidemic in both children and adults, and it is associated with numerous co-morbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, is an independent risk factor for CVD and CVD risks have been also documented in obese children, and is associated with reduced life expectancy. A variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amount. As a whole, overweight/obesity predispose or is associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death through its impact on the cardiovascular system.

【关键词】  congestive heart failure myocardial biology structure

Obesity is becoming a global epidemic, 1,2 and in the United States over the last ten years there have been dramatic increases in obesity in both children and adults. 3-5 Currently overweight and obesity are classified using the body mass index (BMI). In adults, overweight is defined as a BMI of 25.0 to 29.9 kg/m 2; obesity is defined as a BMI 30.0 kg/m 2 ( Table 1 ). 6 The increase in the prevalence of obesity that had not been anticipated has led the American Heart Association to a call for action to curb the consequences of this epidemic. 7,8 Recently the AHA has addressed and reviewed a variety of weight loss approaches for the management and treatment of obesity. 9 Beyond an unfavorable risk factor profile, overweight/obesity also impact the heart structure and function. 10

TABLE 1. Classification of Overweight and Obesity by Percentage of Body Fat, Body Mass Index (BMI), Waist Circumference, and Associated Diseases Risk

See Circulation. 2006;113:898-918.

Obesity as a Metabolic/Genetic Cardiovascular Disease Risk Factor

An explosive increase in the number of people with the Metabolic Syndrome (MetS) has taken place all around the globe. Several definitions of the MetS have been published and this issue has been reviewed lately. 11 The MetS is associated with an increased risk of both diabetes 12 and cardiovascular disease (CVD). 13-16 Abdominal obesity is a risk factor for CVD worldwide, 17,18 but the estimated years of life lost attributable to obesity differs among races and gender. 19 Within a permissive environment, the more common genetic factors involved in obesity regulate the distribution of body fat, the metabolic rate and its response to exercise and diet, and the control of feeding and food preferences. 20,21 There are presently more than 41 sites on the genome that have been identified as possible links to the development of obesity in a favorable environment. 22

Beside an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amount, 23 even in the absence of co-morbidities. As a whole, overweight/obesity predispose or is associated with numerous cardiac complications such as coronary heart disease (CHD), heart failure, and sudden death through its impact on the cardiovascular system.

Cardiomyopathy of Obesity (Adipositas Cordis)

Initially, the fatty heart is probably not an infiltrative process but most likely a metaplasic phenomenon. 24 Cords of cells can gradually accumulate fat between muscle fibers and/or result in myocyte degeneration resulting in cardiac dysfunction. 10 In this situation, small irregular aggregates and bands of adipose tissue separate myocardial cells, a potential result of pressure-induced atrophy from the intervening fat. 25 An alternative explanation explaining the pathophysiology of the cardiomyopathy of obesity is the lipotoxicity of the myocardium induced by free fatty acids, which can cause apoptosis of lipid-laden cells such as cardiomyocytes. 26

Through different mechanisms (increased total blood volume, increased cardiac output, left ventricular hypertrophy , left ventricular diastolic dysfunction, adipositas cordis), obesity may predispose to heart failure. Because dyspnea with exertion and lower extremity edema are often nonspecific signs of heart disease in obesity, 27-29 it may be difficult to clinically assess an obese individual because of several limitations inherent to the subject?s morphology.

Assessment of Obese Individuals and Co-Morbidities

The physical examination and ECG often underestimate the presence and extent of cardiac dysfunction in obese patients. 30

Like physical evaluation, the ECG is influenced by morphological changes induced by obesity such as (1) displacement of the heart by an elevated diaphragm, (2) increased cardiac workload with associated cardiac hypertrophy, (3) increased distance between the heart and the recording electrodes induced by the accumulation of adipose tissue in the subcutaneous tissue of the chest wall (and possibly increased epicardial fat), and (4) the potential associated chronic lung disease secondary to the sleep apnea/hypoventilation syndrome.

There are several changes in the ECG with increasing obesity ( Table 2 ). 31-33 Multiple ECG criteria for LVH are present more regularly in morbid obesity compared with lean individuals but less frequently than might be expected based on the high prevalence of echocardiographic LVH in such patients. 31,34,35 It was proposed that for men, LVH is present by QRS voltage alone when the amplitude of the R wave in lead AVL and the S wave in lead V 3 35 mm. For women, the same criteria 25 mm. 36 Thus, Sokolow-Lyon voltage should be replaced by the Cornell voltage criteria, which seems to be less influenced by the presence of obesity. 37 The impact of weight loss in obese patients on the QRS voltage is not consistent. With weight loss, a decreased amount of fat mass may counterbalance a true decrease in left ventricular mass. 38-40

TABLE 2. ECG Changes That May Occur in Obese Individuals

Echocardiography

In times past, obesity-induced cardiac abnormalities were found only post-mortem. 10 Differentiation between subepicardial adipose tissue and pericardial effusion is often difficult in obese patients, 41,42 and epicardial adipose tissue is known to be a common cause of false-positive effusion. 43,44 The increased intravascular volume in obesity may mask the Doppler-derived abnormalities of diastolic filling. Indexing left ventricular mass using height 2.13 or height 2.7 may be more appropriate than normalization for body surface area or even for height in obese patients, 45,46 but using lean body mass may be even more suitable. 47 Indeed, stroke volume and cardiac output are more strongly related to fat free mass than other variables in both normal weight and overweight individuals. 48

Venous Insufficiency, Venous Thrombosis, and Pulmonary Embolus

A common finding in massive obesity is pedal edema, which may be partly a consequence of elevated ventricular filling pressure, despite elevation in cardiac output. 49,50 However in patients with circadian venous edemas, high volume lymphatic overload (dynamic insufficiency) as well as increased intravascular volume associated with the decreased mobility encountered in obese individuals reducing the pumping function of calf and leg muscles, may result in reflux of blood in the leg veins attributable to venous valvular incompetence. The risk of the severe and sustained lower extremity venous stasis disease in severe obesity is pretibial ulceration and cellulitis. In the absence of right heart failure, surgically-induced weight loss is effective in correcting the venous stasis disease in the majority of patients. 51 The incidence of venous thromboembolism (VTE) is increased in obesity. 52,53 Obesity has also been associated with an increased risk of pulmonary embolism in women, 54 but this is less clear for men. 53

Hypertension

The majority of patients with high blood pressure are overweight, and hypertension is more frequent in obese subjects. 55 A 10 kg higher body weight is associated with a 3.0 mm Hg higher systolic and 2.3 mm Hg higher diastolic blood pressure. These increases translate into an estimated 12% increased risk for CHD and 24% increased risk for stroke. 6 Results from NHANES III reported more specific estimates for the prevalence of high blood pressure per age and BMI group. 56 This increase in blood pressure is greatest when the obesity is of abdominal distribution. 57-61 Factors to be considered in linking obesity to an increase in blood pressure include: (1) direct effects of obesity on hemodynamics: increase in blood volume, stroke volume, and cardiac output, and (2) mechanisms linking obesity and an increase in peripheral vascular resistance: endothelial dysfunction, insulin resistance, sympathetic nervous system, substances released from adipocytes (interleukin -6, tumor necrosis factor -, etc.), and sleep apnea. Regardless of the mechanisms involved, weight loss in obese individuals is associated with a decrease in blood pressure. In 50% or more of individuals, the average decrease in diastolic blood pressure is 1 to 4 mm Hg systolic and 1 to 2 mm Hg diastolic per kilogram of weight reduction as normalization of blood pressure. 62-64 Of note, after the weight loss has ceased, the persistent effect of weight loss on blood pressure may not always be encountered. 65,66

Sleep Apnea

The prevalence of sleep-disordered breathing and sleep disturbances rises dramatically in obese subjects, 67 and obesity is by far the most important modifiable risk factor for sleep-disordered breathing. 68,69 Obese individuals have an increased demand for ventilation and breathing workload, respiratory muscle inefficiency, decreased functional reserve capacity and expiratory reserve volume, and closure of peripheral lung units. These often result in a ventilation perfusion mismatch, especially in the supine position. Obesity is a classical cause of alveolar hypoventilation. Numerous treatments are available for sleep apnea but weight loss in obese patients should always be advocated. 70

Stroke

Numerous studies have reported an association between BMI and waist-to-hip ratio and stroke. 71-79 Each 1-unit increase in BMI was associated with a multiple adjusted increase of 4% in the risk of ischemic stroke and 6% for hemorrhagic stroke. However, stroke severity for ischemic stroke was not associated with BMI. 80 The increase of stroke in obesity may be predicted by the prothrombotic/proinflammatory state that so often accompanies excessive adipose tissue accumulation. 81,82

Coronary Artery Disease

Examination of arteries post-mortem from individuals 15 to 34 years of age (Determinants of Atherosclerosis in Youth study) who died from accidental injuries, homicides, or suicides revealed that the extent of fatty streaks and advanced lesions (fibrous plaques and plaques with calcification or ulceration) in the right coronary artery (RCA) and in the abdominal aorta were associated with obesity and with the size of the abdominal panniculus. 83-86 Black subjects had more extensive fatty streaks than white subjects in all arterial segments examined, and men did have more extensive raised lesions in the RCA than women. 87 Of note, it was reported that the maximal density of macrophages/mm 2 in the lesions was associated with visceral obesity. 88

Raised lesions in coronary arteries observed in young women lagged behind by 10 to 20 years to those seen in young men. 17,18,89,90 The preferential deposition of fat centrally after menopause may in part explain why the risk for CHD events increases later in women. 17,18,91 Prospective studies that have reported follow-up data over more than two decades such as Framingham Heart Study, the Manitoba Study, and the Harvard School of Public Health Nurses Study have documented that obesity is an independent predictor of clinical CHD. 92-95 In contrast, in patients with known CVD or after acute myocardial infarction, overall obesity as assessed by BMI is inversely related to mortality, 96,97 whereas abdominal obesity appears to be an independent predictor of all-cause mortality in men and perhaps also in women. In the Trandolapril Cardiac Evaluation (TRACE) register, the mortality rate was increased 23% compared with patients who were not abdominally obese.

Coronary Artery Disease Revascularization Procedure in Obesity

Today, obesity is encountered more frequently in the catheterization laboratory where obese patients are younger with more co-morbidities, but showing more single-vessel disease at baseline. 98,99 Abnormal glucose tolerance may be an important determinant for long-term prognosis after coronary angioplasty, 100 which may be dependent on the features of the MetS. 101 After coronary artery bypass, the components of the insulin resistance syndrome are associated with angiographic progression of atherosclerosis in non-grafted coronary arteries. 102 Therefore, abnormalities of glucose metabolism with features of the MetS could modulate the extent of atherosclerosis within the coronary artery tree and modulate acute coronary syndrome events. 103,104 In contrast to frequent beliefs, obesity is not associated with increased mortality or postoperative cerebrovascular accidents after CABG. 105,106 However, an increased incidence of sternal and superficial wound infection, saphenous vein harvest site infection, and atrial dysrhythmias was seen. 107-109 35 kg/m 2 ) are more likely to have prolonged mechanical ventilation and longer post-operative stay. 109

Congestive Heart Failure

Elevated BMI predisposes to congestive heart failure (CHF) by promoting hypertension, diabetes, and CHD. 91,110-113 It is estimated that there is an increase in the risk of CHF of 5% for men and 7% for women for each increment of 1 U of BMI with the existence of a continuous gradient without evidence of a threshold. 111 In contrast, once the patient presents with CHF, the presence of obesity may not adversely affect the patient?s outcome. 114-116 Indeed, among patients with CHF, subjects with higher BMI are at decreased risk for death and hospitalization compared with patients with a "healthy" BMI. 114,116-120 140% ideal body weight) may increase morbidity and mortality after heart transplantation. 121

Arrythmias

Weight-stable obese subjects have an increased risk of arrhythmias and sudden death, even in the absence of cardiac dysfunction, 122,123 and the risk of sudden cardiac death with increasing weight is seen in both genders. 92 In the Framingham study, the annual sudden cardiac mortality rate in obese men and women was estimated to be 40 times higher than the rate of unexplained cardiac arrest in a matched non-obese population. 92,122 Specifically, in severely obese men, a 6- and 12-fold excess mortality rate was reported in the age group 35 to 44 and 25 to 34 years, respectively. 124

Prolonged QT c interval was observed in 30% of subjects with impaired glucose tolerance, 125 and there is a positive association between BMI and QT c. 126 When visceral obesity or insulin levels increase, sympathovagal balance may be the best explanation for changes in QT c. 127 The clinical significance of obesity-associated QT prolongation and the mechanisms involved remain speculative. High glucose concentrations may promote increased vasomotor tone and ventricular instability by reducing nitric oxide availability. 128,129 Moreover, because extremely obese patients often have a dilated cardiomyopathy, fatal arrhythmias may be the most frequent cause of death. 123,130 Obesity and cardiac autonomic nervous system are intrinsically related. A 10% increase in body weight is associated with a decline in parasympathetic tone accompanied by a rise in mean heart rate, and conversely heart rate declines during weight reduction. 131 It was demonstrated that a 10% weight loss in severely obese patients is associated with significant improvement in autonomic nervous system cardiac modulation. 132

Weight Loss

Cardiopulmonary Impact of Weight Reduction Therapy

Intentional weight loss in obese patients can improve or prevent many of the obesity-related risk factors for CHD. 9,133 Current therapies available for weight management that cause weight loss by inducing a negative energy balance include: dietary intervention, physical activity, pharmacotherapy, and surgery. Behavior modification to enhance dietary and activity compliance is an important component of all of these treatments. Diverse modalities had been addressed lately by the American Heart Association. 9 At present, the therapeutic intervention used does not appear to be relevant to the benefit of weight reduction on the cardiovascular system with a few exceptions to be noted below.

Surgically-induced weight loss produces a decrease in resting oxygen consumption and cardiac output that is proportional to the magnitude of weight loss. 134,135 Table 3 enumerates the beneficial impacts of weight loss on the cardiovascular system. Sympathetic mechanisms have been implicated in the development of LVH, 136 and weight reduction in obese subjects reduces the indices of sympathetic activity. The renin-angiotensin system may also be involved in the pathogenesis of LVH, and weight reduction may decrease plasma renin activity and aldosterone levels. 137 The improvement in hyperinsulinemia may also be related to the reduction in left ventricular mass in hypertensive obese subjects. 138 A reduction in angiotensin-converting enzyme activity after weight reduction could also be important. 139

TABLE 3. Benefits of Weight Reduction on the Cardiovascular System

Risks of Weight Loss

Weight loss through different modalities, ie, starvation, 40,140 liquid protein diets, 38,39 very low calorie diets, and even obesity surgery, 141 has been associated with prolongation of the QT c interval. Most importantly, liquid protein diets that have been associated with potentially life-threatening arrhythmias were only suspected after a 24-hour Holter recording. 142 These diets are still in use today. Accordingly, more care is now taken to ensure micronutrient supplementation and to monitor for adverse effects.

Fenfluramine and dexfenfluramine, which reduce appetite by enhancing serotonin at nerve terminals in the hypothalamus, were removed from the marketplace after reports of cardiac-valve disorders. 143 There was also an increased risk of primary pulmonary hypertension documented. 144-147

Sibutramine hydrochloride and orlistat are the latest drugs available on the market for the treatment of obesity and have been shown to be effective in the treatment of obesity and associated co-morbidities. 148,149 Sibutramine hydrochloride, a centrally acting drug, 150 which is approved for long-term use, has not been associated with valve abnormalities. 151,152 However, increases in blood pressure and heart rate may occur with the use of this drug, 152,153 and like phentermine, sibutramine should not be used in patients with untreated hypertension, CHD, CHF, arrhythmias, or stroke. 150 The impacts of the endocannabinoid receptor antagonists in the treatment of obesity on heart structure and function are not known.

Obesity and the Future of Health Care Services

Health service usage and medical costs associated with obesity and related diseases have and will increase dramatically. 154 Waist circumference may be a better predictor of health care costs than the widely used BMI. 155 Increased physical activity early in life may become the cost effective nonpharmacological avenue to combat obesity. 156 Body weight normalization should not be the primary target but rather some weight loss which can lead to substantial improvements in risk factors. 157 Aside from enhanced metabolic profile, weight loss impacts favorably on the cardiovascular system through diverse mechanisms. Of interest, even if weight loss is minimal, obese individuals with a good level of cardiorespiratory fitness show a reduced risk for cardiovascular mortality compared with lean poorly fit subjects. 158 Although there have been no prospective trials to convincingly show changes in mortality with weight loss in obese patients, it has been reported that individuals who attempted intentionally to lose weight present significantly lower all-cause mortality, independent of weight change. 159-161

Conclusions

Obesity is a chronic metabolic disorder associated with CVD and increased morbidity and mortality. It is apparent that a variety of adaptations/alterations in cardiac structure and function occur as excessive adipose tissue accumulates, even in the absence of systemic hypertension or underlying organic heart disease. To meet increased metabolic needs, circulating blood volume, plasma volume, and cardiac output all increase. The increase in blood volume in turn increases venous return to the right and the left ventricles, eventually producing dilatation of these cardiac cavities, increasing wall tension. This leads to LVH, which is accompanied by a decrease in diastolic chamber compliance, eventually resulting in an increase in left ventricular filling pressure and left ventricular enlargement. As long as LVH adapts to left ventricular chamber enlargement, systolic function is preserved. When LVH fails to keep pace with progressive left ventricular dilatation, wall tension increases even more and systolic dysfunction may ensue. Systemic hypertension, pulmonary hypertension (left ventricular failure, chronic hypoxia), and CHD all occur with disproportionately high frequency in obese individuals and may cause or contribute to alterations in cardiac structure and function. There is also an increased risk of sudden cardiac death in obesity.

Hopefully, within the next decade, new information may be provided that weight reduction is beneficial for hard CVD outcomes, ie, CHD events, CHD death, CHF, stroke, and total mortality. Until then, the clinical approach must hope that such a favorable result will ensue. The problem of overweight/obesity has been identified as one of the major CVD risk factors since 1998, and although we understand to some extent the pathophysiological link between overweight/obesity and many forms of CVD, a number of remaining scientific questions need to be addressed for us to have a more complete understanding of the relationship between overweight/obesity and CVD.

【参考文献】
  Eckel RH, York DA, Rossner S, Hubbard V, Caterson I, St Jeor ST, Hayman LL, Mullis RM, Blair SN; American Heart Association. Prevention Conference VII: Obesity, a worldwide epidemic related to heart disease and stroke: executive summary. Circulation. 2004; 110: 2968-2975.

World Health Organization. Obesity: Preventing and managing the global epidemic. [WHO Technical report series #894]. 2000. Geneva. World Health Organization.

Engeland A, Bjorge T, Sogaard AJ, Tverdal A. Body mass index in adolescence in relation to total mortality: 32-year follow-up of 227,000 Norwegian boys and girls. Am J Epidemiol. 2003; 157: 517-523.

Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. J Am Med Assoc. 2002; 288: 1723-1727.

Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord. 1998; 22: 39-47.

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults-The Evidence Report. National Institutes of Health. Obes Res. 1998; Suppl 2: 51S-209S.

Eckel RH. Obesity and heart disease: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1997; 96: 3248-3250.

Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. AHA Nutrition Committee. Circulation. 1998; 97: 2099-2100.

Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH; American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the Am Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the Am College of Cardiology Foundation. Circulation. 2004; 110: 2952-2967.

Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH; American Heart Association; Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006; 113: 898-918.

Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365: 1415-1428.

Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA; American Heart Association; National Heart, Lung, and Blood Institute; American Diabetes Association. Clinical management of metabolic syndrome: report of the Am Heart Association/National Heart, Lung, and Blood Institute/Am Diabetes Association conference on scientific issues related to management. Circulation. 2004; 109: 551-556.

Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001; 24: 683-689.

Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc. 2002; 288: 2709-2716.

Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TR, Beere PA, Gotto AM, Clearfield M; 4S Group and the AFCAPS/TexCAPS Research Group. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol. 2004; 93: 136-141.

Malik S, Wong ND, Franklin SS, Kamath TV, L?Italien GJ, Pio JR, Williams GR. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation. 2004; 110: 1245-1250.

Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364: 937-952.

Yusuf S, Vaz M, Pais P. Tackling the challenge of cardiovascular disease burden in developing countries. Am Heart J. 2004; 148: 1-4.

Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. J Am Med Assoc. 2003; 289: 187-193.

Vohl MC, Sladek R, Robitaille J, Gurd S, Marceau P, Richard D, Hudson TJ, Tchernof A. A survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men. Obes Res. 2004; 12: 1217-1222.

Bouchard L, Drapeau V, Provencher V, Lemieux S, Chagnon Y, Rice T, Rao DC, Vohl MC, Tremblay A, Bouchard C, Perusse L. Neuromedin beta: a strong candidate gene linking eating behaviors and susceptibility to obesity. Am J Clin Nutr. 2004; 80: 1478-1486.

Snyder EE, Walts B, Perusse L, Chagnon YC, Weisnagel SJ, Rankinen T, Bouchard C. The human obesity gene map: the 2003 update. Obes Res. 2004; 12: 369-439.

Poirier P, Martin J, Marceau P, Biron S, Marceau S. Impact of bariatric surgery on cardiac structure, function and clinical manifestations in morbid obesity. Expert Rev Cardiovasc Ther. 2004; 2: 193-201.

Carpenter CL. Myocardial fat infiltration. Am Heart J. 1962; 63: 491-496.

Dervan JP, Ilercil A, Kane PB, Anagnostopoulos C. Fatty infiltration: another restrictive cardiomyopathic pattern. Cathet Cardiovasc Diagn. 1991; 22: 184-189.

Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A. 2000; 97: 1784-1789.

Poirier P, Alpert MA. Heart disease. In: Eckel RH, editor. Obesity: Mechanisms and Clinical Management. Philadelphia: Williams & Wilkins, 2003: 181-201.

Karason K, Lindroos AK, Stenlof K, Sjostrom L. Relief of cardiorespiratory symptoms and increased physical activity after surgically induced weight loss. Results from the Swedish Obese Subjects Study. Arch Intern Med. 2000; 160: 1797-1802.

Poirier P, Despres JP. Exercise in weight management of obesity. Cardiol Clin. 2001; 19: 459-470.

Alpert MA. Obesity cardiomyopathy; pathophysiology and evolution of the clinical syndrome. Am J Med Sci. 2001; 321: 225-236.

Alpert MA, Terry BE, Cohen MV, Fan TM, Painter JA, Massey CV. The electrocardiogram in morbid obesity. Am J Cardiol. 2000; 85: 908-910.

Eisenstein I, Edelstein J, Sarma R, Sanmarco M, Selvester RH. The electrocardiogram in obesity. J Electrocardiol. 1982; 15: 115-118.

Master AM, Oppenheimer ET. A study of obesity: circulatory, roentgen-ray and electrocardiographic investigations. J Am Med Assoc. 1929; 92: 1652-1656.

Alpert MA, Alexander JK. The heart and lung in obesity. Armonk: Futura Publishing Company, 1998.

Nath A, Alpert MA, Terry BE, Kelly DL. Sensitivity and specificity of electrocardiographic criteria for left and right ventricular hypertrophy in morbid obesity. Am J Cardiol. 1988; 62: 126-130.

Casale PN, Devereux RB, Kligfield P, Eisenberg RR, Miller DH, Chaudhary BS, Phillips MC. Electrocardiographic detection of left ventricular hypertrophy: development and prospective validation of improved criteria. J Am Coll Cardiol. 1985; 6: 572-580.

Abergel E, Tase M, Menard J, Chatellier G. Influence of obesity on the diagnostic value of electrocardiographic criteria for detecting left ventricular hypertrophy. Am J Cardiol. 1996; 77: 739-744.

Sours HE, Frattali VP, Brand CD, Feldman RA, Forbes AL, Swanson RC, Paris AL. Sudden death associated with very low calorie weight reduction regimens. Am J Clin Nutr. 1981; 34: 453-461.

Isner JM, Sours HE, Paris AL, Ferrans VJ, Roberts WC. Sudden, unexpected death in avid dieters using the liquid-protein-modified-fast diet. Observations in 17 patients and the role of the prolonged QT interval. Circulation. 1979; 60: 1401-1412.

Garnett ES, Barnard DL, Ford J, Goodbody RA, Woodehouse MA. Gross fragmentation of cardiac myofibrils after therapeutic starvation for obesity. Lancet. 1969; 1: 914-916.

Alpert MA, Kelly DL. Value and limitations of echocardiography assessment of obese patients. Echocardiography. 1986; 3: 261-272.

Ansari A, Rholl AO. Pseudopericardial effusion: echocardiographic and computed tomographic correlations. Clin Cardiol. 1986; 9: 551-555.

House AA, Walley VM. Right heart failure due to ventricular adiposity: ?adipositas cordis?-an old diagnosis revisited. Can J Cardiol. 1996; 12: 485-489.

Savage DD, Garrison RJ, Brand F, Anderson SJ, Castelli WP, Kannel WB, Feinleib M. Prevalence and correlates of posterior extra echocardiographic spaces in a free-living population based sample (the Framingham study). Am J Cardiol. 1983; 51: 1207-1212.

de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol. 1992; 20: 1251-1260.

Lauer MS, Anderson KM, Larson MG, Levy D. A new method for indexing left ventricular mass for differences in body size. Am J Cardiol. 1994; 74: 487-491.

Hense HW, Gneiting B, Muscholl M, Broeckel U, Kuch B, Doering A, Riegger GA, Schunkert H. The associations of body size and body composition with left ventricular mass: impacts for indexation in adults. J Am Coll Cardiol. 1998; 32: 451-457.

Collis T, Devereux RB, Roman MJ, de Simone G, Yeh J, Howard BV, Fabsitz RR, Welty TK. Relations of stroke volume and cardiac output to body composition: the strong heart study. Circulation. 2001; 103: 820-825.

de Divitiis O, Fazio S, Petitto M, Maddalena G, Contaldo F, Mancini M. Obesity and cardiac function. Circulation. 1981; 64: 477-482.

Nakajima T, Fujioka S, Tokunaga K, Matsuzawa Y, Tarui S. Correlation of intraabdominal fat accumulation and left ventricular performance in obesity. Am J Cardiol. 1989; 64: 369-373.

Sugerman HJ, Sugerman EL, Wolfe L, Kellum JM Jr, Schweitzer MA, DeMaria EJ. Risks and benefits of gastric bypass in morbidly obese patients with severe venous stasis disease. Ann Surg. 2001; 234: 41-46.

Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002; 162: 1182-1189.

Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: ?the study of men born in 1913?. Arch Intern Med. 1999; 159: 1886-1890.

Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. A prospective study of risk factors for pulmonary embolism in women. J Am Med Assoc. 1997; 277: 642-645.

Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH. Weight and blood pressure. Findings in hypertension screening of 1 million Americans. J Am Med Assoc. 1978; 240: 1607-1610.

Brown CD, Higgins M, Donato KA, Rohde FC, Garrison R, Obarzanek E, Ernst ND, Horan M. Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res. 2000; 8: 605-619.

King GE. Errors in clinical measurement of blood pressure in obesity. Clin Sci. 1967; 32: 223-237.

Bjorntorp P. Classification of obese patients and complications related to the distribution of surplus fat. Nutrition. 1990; 6: 131-137.

Bjorntorp P. Obesity and adipose tissue distribution as risk factors for the development of disease. A review. Infusionstherapie. 1990; 17: 24-27.

Poirier P, Lemieux I, Mauriege P, Dewailly E, Blanchet C, Bergeron J, Despres JP. Impact of waist circumference on the relationship between blood pressure and insulin: the Quebec Health Survey. Hypertension. 2005; 45: 363-367.

Muller DC, Elahi D, Pratley RE, Tobin JD, Andres R. An epidemiological test of the hyperinsulinemia-hypertension hypothesis. J Clin Endocrinol Metab. 1993; 76: 544-548.

Schotte DE, Stunkard AJ. The effects of weight reduction on blood pressure in 301 obese patients. Arch Intern Med. 1990; 150: 1701-1704.

Novi RF, Porta M, Lamberto M, Molinatti GM. Reductions of body weight and blood pressure in obese hypertensive patients treated by diet. A retrospective study. Panminerva Med. 1989; 31: 13-15.

Staessen J, Fagard R, Amery A. The relationship between body weight and blood pressure. J Hum Hypertens. 1988; 2: 207-217.

Pontiroli AE, Pizzocri P, Saibene A, Girola A, Koprivec D, Fragasso G. Left ventricular hypertrophy and QT interval in obesity and in hypertension: effects of weight loss and of normalisation of blood pressure. Int J Obes Relat Metab Disord. 2004; 28: 1118-1123.

Sjostrom CD, Peltonen M, Wedel H, Sjostrom L. Differentiated long-term effects of intentional weight loss on diabetes and hypertension. Hypertension. 2000; 36: 20-25.

Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med. 1994; 154: 1705-1711.

Bearpark H, Elliott L, Grunstein R, Cullen S, Schneider H, Althaus W, Sullivan C. Snoring and sleep apnea. A population study in Australian men. Am J Respir Crit Care Med. 1995; 151: 1459-1465.

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993; 328: 1230-1235.

Strollo PJJ, Rogers RM. Obstructive sleep apnea. N Engl J Med. 1996; 334: 99-104.

Abbott RD, Behrens GR, Sharp DS, Rodriguez BL, Burchfiel CM, Ross GW, Yano K, Curb JD. Body mass index and thromboembolic stroke in nonsmoking men in older middle age. The Honolulu Heart Program. Stroke. 1994; 25: 2370-2376.

Rhoads GG, Kagan A. The relation of coronary disease, stroke, and mortality to weight in youth and in middle age. Lancet. 1983; 1: 492-495.

Shinton R, Shipley M, Rose G. Overweight and stroke in the Whitehall study. J Epidemiol Community Health. 1991; 45: 138-142.

Rexrode KM, Hennekens CH, Willett WC, Colditz GA, Stampfer MJ, Rich-Edwards JW, Speizer FE, Manson JE. A prospective study of body mass index, weight change, and risk of stroke in women. J Am Med Assoc. 1997; 277: 1539-1545.

Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. BMJ (Clin Res Ed). 1984; 289: 1257-1261.

Folsom AR, Prineas RJ, Kaye SA, Munger RG. Incidence of hypertension and stroke in relation to body fat distribution and other risk factors in older women. Stroke. 1990; 21: 701-706.

Terry RB, Page WF, Haskell WL. Waist/hip ratio, body mass index and premature cardiovascular disease mortality in US Army veterans during a twenty-three year follow-up study. Int J Obes Relat Metab Disord. 1992; 16: 417-423.

Walker SP, Rimm EB, Ascherio A, Kawachi I, Stampfer MJ, Willett WC. Body size and fat distribution as predictors of stroke among US men. Am J Epidemiol. 1996; 144: 1143-1150.

Pyorala M, Miettinen H, Laakso M, Pyorala K. Hyperinsulinemia and the risk of stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Stroke. 1998; 29: 1860-1866.

Kurth T, Gaziano JM, Berger K, Kase CS, Rexrode KM, Cook NR, Buring JE, Manson JE. Body mass index and the risk of stroke in men. Arch Intern Med. 2002; 162: 2557-2562.

Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D?Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. 2001; 32: 2575-2579.

Sriram K, Benkovic SA, Miller DB, O?Callaghan JP. Obesity exacerbates chemically induced neurodegeneration. Neuroscience. 2002; 115: 1335-1346.

McGill HC Jr, McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr. 2000; 72: 1307S-1315S.

Berenson GS. Bogalusa Heart Study: a long-term community study of a rural biracial (black/white) population. Am J Med Sci. 2001; 322: 267-274.

Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea. J Am Med Assoc. 1953; 152: 1090-1093.

McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong JP. Relation of glycohemoglobin and adiposity to atherosclerosis in youth. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol. 1995; 15: 431-440.

Zieske AW, Malcom GT, Strong JP. Natural history and risk factors of atherosclerosis in children and youth: the PDAY study. Pediatr Pathol Mol Med. 2002; 21: 213-237.

Kortelainen ML, Sarkioja T. Visceral fat and coronary pathology in male adolescents. Int J Obes Relat Metab Disord. 2001; 25: 228-232.

McGill HC Jr, McMahan CA, Herderick EE, Zieske AW, Malcom GT, Tracy RE, Strong JP; Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation. 2002; 105: 2712-2718.

Kannel WB. The Framingham Study: historical insight on the impact of cardiovascular risk factors in men versus women. J Gend Specif Med. 2002; 5: 27-37.

Kortelainen ML. Myocardial infarction and coronary pathology in severely obese people examined at autopsy. Int J Obes Relat Metab Disord. 2002; 26: 73-79.

Rabkin SW, Mathewson FA, Hsu PH. Relation of body weight to development of ischemic heart disease in a cohort of young North Am men after a 26 year observation period: the Manitoba Study. Am J Cardiol. 1977; 39: 452-458.

Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983; 67: 968-977.

Wilson PW, D?Agostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med. 2002; 162: 1867-1872.

Manson JE, Colditz GA, Stampfer MJ, Willett WC, Rosner B, Monson RR, Speizer FE, Hennekens CH. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med. 1990; 322: 882-889.

Dagenais GR, Yi Q, Mann JF, Bosch J, Pogue J, Yusuf S. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J. 2005; 149: 54-60.

Kragelund C, Hassager C, Hildebrandt P, Torp-Pedersen C, Kober L; TRACE study group. Impact of obesity on long-term prognosis following acute myocardial infarction. Int J Cardiol. 2005; 98: 123-131.

Eisenstein EL, Shaw LK, Nelson CL, Anstrom KJ, Hakim Z, Mark DB. Obesity and long-term clinical and economic outcomes in coronary artery disease patients. Obes Res. 2002; 10: 83-91.

Gruberg L, Weissman NJ, Waksman R, Fuchs S, Deible R, Pinnow EE, Ahmed LM, Kent KM, Pichard AD, Suddath WO, Satler LF, Lindsay J Jr. The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox? J Am Coll Cardiol. 2002; 39: 578-584.

Otsuka Y, Miyazaki S, Okumura H, Yasuda S, Daikoku S, Morii I, Sutani Y, Goto Y, Nonogi H. Abnormal glucose tolerance, not small vessel diameter, is a determinant of long-term prognosis in patients treated with balloon coronary angioplasty. Eur Heart J. 2000; 21: 1790-1796.

St-Pierre J, Lemieux I, Vohl MC, Perron P, Tremblay G, Despres JP, Gaudet D. Contribution of abdominal obesity and hypertriglyceridemia to impaired fasting glucose and coronary artery disease. Am J Cardiol. 2002; 90: 15-18.

Korpilahti K, Syvanne M, Engblom E, Hamalainen H, Puukka P, Ronnemaa T. Components of the insulin resistance syndrome are associated with progression of atherosclerosis in non-grafted arteries 5 years after coronary artery bypass surgery. Eur Heart J. 1998; 19: 711-719.

Kowalska I, Prokop J, Bachorzewska-Gajewska H, Telejko B, Kinalskal I, Kochman W, Musial W. Disturbances of glucose metabolism in men referred for coronary arteriography. Postload glycemia as predictor for coronary atherosclerosis. Diabetes Care. 2001; 24: 897-901.

Qiao Q, Pyorala K, Pyorala M, Nissinen A, Lindstrom J, Tilvis R, Tuomilehto J. Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. Eur Heart J. 2002; 23: 1267-1275.

Ascione R, Angelini GD. Is obesity still a risk factor for patients undergoing coronary surgery? Ital Heart J. 2003; 4: 824-828.

Rockx MA, Fox SA, Stitt LW, Lehnhardt KR, McKenzie FN, Quantz MA, Menkis AH, Novick RJ. Is obesity a predictor of mortality, morbidity and readmission after cardiac surgery? Can J Surg. 2004; 47: 34-38.

Moulton MJ, Creswell LL, Mackey ME, Cox JL, Rosenbloom M. Obesity is not a risk factor for significant adverse outcomes after cardiac surgery. Circulation. 1996; 94: II87-II92.

Birkmeyer NJ, Charlesworth DC, Hernandez F, Leavitt BJ, Marrin CA, Morton JR, Olmstead EM, O?Connor GT. Obesity and risk of adverse outcomes associated with coronary artery bypass surgery. Northern New England Cardiovascular Disease Study Group. Circulation. 1998; 97: 1689-1694.

Kuduvalli M, Grayson AD, Oo AY, Fabri BM, Rashid A. Risk of morbidity and in-hospital mortality in obese patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg. 2002; 22: 787-793.

He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001; 161: 996-1002.

Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med. 2002; 347: 305-313.

Chen YT, Vaccarino V, Williams CS, Butler J, Berkman LF, Krumholz HM. Risk factors for heart failure in the elderly: a prospective community-based study. Am J Med. 1999; 106: 605-612.

Wilhelmsen L, Rosengren A, Eriksson H, Lappas G. Heart failure in the general population of men-morbidity, risk factors and prognosis. J Intern Med. 2001; 249: 253-261.

Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol. 2001; 38: 789-795.

Alla F, Briancon S, Juilliere Y, Mertes PM, Villemot JP, Zannad F. Differential clinical prognostic classifications in dilated and ischemic advanced heart failure: the EPICAL study. Am Heart J. 2000; 139: 895-904.

Osman AF, Mehra MR, Lavie CJ, Nunez E, Milani RV. The incremental prognostic importance of body fat adjusted peak oxygen consumption in chronic heart failure. J Am Coll Cardiol. 2000; 36: 2126-2131.

Lissin LW, Gauri AJ, Froelicher VF, Ghayoumi A, Myers J, Giacommini J. The prognostic value of body mass index and standard exercise testing in male veterans with congestive heart failure. J Card Fail. 2002; 8: 206-215.

Davos CH, Doehner W, Rauchhaus M, Cicoira M, Francis DP, Coats AJ, Clark AL, Anker SD. Body mass and survival in patients with chronic heart failure without cachexia: the importance of obesity. J Card Fail. 2003; 9: 29-35.

Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol. 2003; 91: 891-894.

Mosterd A, Cost B, Hoes AW, de Bruijne MC, Deckers JW, Hofman A, Grobbee DE. The prognosis of heart failure in the general population: The Rotterdam Study. Eur Heart J. 2001; 22: 1318-1327.

Grady KL, White-Williams C, Naftel D, Costanzo MR, Pitts D, Rayburn B, VanBakel A, Jaski B, Bourge R, Kirklin J. Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality: a multi-institutional study of preoperative weight-height indices. Cardiac Transplant Research Database (CTRD) Group. J Heart Lung Transplant. 1999; 18: 750-763.

Kannel WB, Plehn JF, Cupples LA. Cardiac failure and sudden death in the Framingham Study. Am Heart J. 1988; 115: 869-875.

Messerli FH, Nunez BD, Ventura HO, Snyder DW. Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity. Arch Intern Med. 1987; 147: 1725-1728.

Drenick EJ, Bale GS, Seltzer F, Johnson DG. Excessive mortality and causes of death in morbidly obese men. J Am Med Assoc. 1980; 243: 443-445.

Brown DW, Giles WH, Greenlund KJ, Valdez R, Croft JB. Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the Third National Health and Nutrition Examination Survey. J Cardiovasc Risk. 2001; 8: 227-233.

el-Gamal A, Gallagher D, Nawras A, Gandhi P, Gomez J, Allison DB, Steinberg JS, Shumacher D, Blank R, Heymsfield SB. Effects of obesity on QT, RR, and QTc intervals. Am J Cardiol. 1995; 75: 956-959.

Esposito K, Nicoletti G, Marzano S et al. Autonomic dysfunction associates with prolongation of QT intervals and blunted night BP in obese women with visceral obesity. J Endocrinol Invest. 2002; 25: RC32-RC35.

D?Amico M, Marfella R, Nappo F, Di Filippo C, De Angelis L, Berrino L, Rossi F, Giugliano D. High glucose induces ventricular instability and increases vasomotor tone in rats. Diabetologia. 2001; 44: 464-470.

Marfella R, Nappo F, De Angelis L, Siniscalchi M, Rossi F, Giugliano D. The effect of acute hyperglycaemia on QTc duration in healthy man. Diabetologia. 2000; 43: 571-575.

Messerli FH, Sundgaard-Riise K, Reisin ED, Dreslinski GR, Ventura HO, Oigman W, Frohlich ED, Dunn FG. Dimorphic cardiac adaptation to obesity and arterial hypertension. Ann Intern Med. 1983; 99: 757-761.

Hirsch J, Leibel RL, Mackintosh R, Aguirre A. Heart rate variability as a measure of autonomic function during weight change in humans. Am J Physiol. 1991; 261: R1418-R1423.

Poirier P, Hernandez TL, Weil KM, Shepard TJ, Eckel RH. Impact of diet-induced weight loss on the cardiac autonomic nervous system in severe obesity. Obes Res. 2003; 11: 1040-1047.

Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD, Sullivan M, Wedel H; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004; 351: 2683-2693.

Backman L, Freyschuss U, Hallberg D, Melcher A. Reversibility of cardiovascular changes in extreme obesity. Effects of weight reduction through jejunoileostomy. Acta Med Scand. 1979; 205: 367-373.

Backman L, Freyschuss U, Hallberg D, Melcher A. Cardiovascular function in extreme obesity. Acta Med Scand. 1973; 193: 437-446.

Benjamin EJ, Levy D. Why is left ventricular hypertrophy so predictive of morbidity and mortality? Am J Med Sci. 1999; 317: 168-175.

Tuck ML, Sowers J, Dornfeld L, Kledzik G, Maxwell M. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med. 1981; 304: 930-933.

Sasson Z, Rasooly Y, Bhesania T, Rasooly I. Insulin resistance is an important determinant of left ventricular mass in the obese. Circulation. 1993; 88: 1431-1436.

Harp JB, Henry SA, DiGirolamo M. Dietary weight loss decreases serum angiotensin-converting enzyme activity in obese adults. Obes Res. 2002; 10: 985-990.

Pringle TH, Scobie IN, Murray RG, Kesson CM, Maccuish AC. Prolongation of the QT interval during therapeutic starvation: a substrate for malignant arrhythmias. Int J Obes. 1983; 7: 253-261.

Drenick EJ, Fisler JS. Sudden cardiac arrest in morbidly obese surgical patients unexplained after autopsy. Am J Surg. 1988; 155: 720-726.

Lantigua RA, Amatruda JM, Biddle TL, Forbes GB, Lockwood DH. Cardiac arrhythmias associated with a liquid protein diet for the treatment of obesity. N Engl J Med. 1980; 303: 735-738.

From the Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services interim public health recommendations. J Am Med Assoc. 1997; 278: 1729-1731.

Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997; 337: 581-588.

Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med. 1998; 339: 725-732.

Khan MA, Herzog CA, St Peter JV, Hartley GG, Madlon-Kay R, Dick CD, Asinger RW, Vessey JT. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med. 1998; 339: 713-718.

Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996; 335: 609-616.

Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998; 352: 167-172.

James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet. 2000; 356: 2119-2125.

McNeely W, Goa KL. Sibutramine. A review of its contribution to the management of obesity. Drugs. 1998; 56: 1093-1124.

Bach DS, Rissanen AM, Mendel CM, Shepherd G, Weinstein SP, Kelly F, Seaton TB, Patel B, Pekkarinen TA, Armstrong WF. Absence of cardiac valve dysfunction in obese patients treated with sibutramine. Obes Res. 1999; 7: 363-369.

Zannad F, Gille B, Grentzinger A, Bruntz JF, Hammadi M, Boivin JM, Hanotin C, Igau B, Drouin P. Effects of sibutramine on ventricular dimensions and heart valves in obese patients during weight reduction. Am Heart J. 2002; 144: 508-515.

Atkinson RL. Use of drugs in the treatment of obesity. Annu Rev Nutr. 1997; 17: 383-403.

Wang F, Schultz AB, Musich S, McDonald T, Hirschland D, Edington DW. The relationship between National Heart, Lung, and Blood Institute Weight Guidelines and concurrent medical costs in a manufacturing population. Am J Health Promot. 2003; 17: 183-189.

Cornier MA, Tate CW, Grunwald GK, Bessesen DH. Relationship between waist circumference, body mass index, and medical care costs. Obes Res. 2002; 10: 1167-1172.

Mitchell BM, Gutin B, Kapuku G, Barbeau P, Humphries MC, Owens S, Vemulapalli S, Allison J. Left ventricular structure and function in obese adolescents: relations to cardiovascular fitness, percent body fat, and visceral adiposity, and effects of physical training. Pediatrics. 2002; 109: E73.

Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB, McCartney JS, Bales CW, Henes S, Samsa GP, Otvos JD, Kulkarni KR, Slentz CA. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med. 2002; 347: 1483-1492.

Lee CD, Blair SN, Jackson AS. Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men. Am J Clin Nutr. 1999; 69: 373-380.

Gregg EW, Gerzoff RB, Thompson TJ, Williamson DF. Intentional weight loss and death in overweight and obese u.s. Adults 35 years of age and older. Ann Intern Med. 2003; 138: 383-389.

Williamson DF, Pamuk E, Thun M, Flanders D, Byers T, Heath C. Prospective study of intentional weight loss and mortality in never-smoking overweight US white women aged 40-64 years. Am J Epidemiol. 1995; 141: 1128-1141.

Williamson DF, Thompson TJ, Thun M, Flanders D, Pamuk E, Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care. 2000; 23: 1499-1504.

作者单位：Paul Poirier; Thomas D. Giles; George A. Bray; Yuling Hong; Judith S. Stern; F. Xavier Pi-Sunyer; Robert H. EckelFrom the Quebec Heart and Lung Institute, Sainte-Foy.