Obesity and cardiovascular disease

Department of Internal Medicine, Wayne State University School of Medicine, 4201 St. Antoine, UHC-4H, Detroit, MI 48201. Fax 313-993-0903; e-mail sowers{at}oncgate.roc.wayne.edu.

Abstract

Obesity, diabetes mellitus, and hypertension are common, interrelated medical problems in Westernized, industrialized societies. These interrelated medical conditions are associated with an increased risk of cardiovascular disease and are more prevalent in several minority groups, including African-American and Hispanic populations. The associated cardiovascular risks of these problems are more thoroughly addressed in another review in this supplement. Obesity markedly enhances the development of Type 2 diabetes. Moreover, it enhances the cardiovascular risk associated with other risk factors, such as hypertension and dyslipidemia. Weight reduction in association with an aerobic exercise program improves metabolic abnormalities and reduces blood pressure in individuals with diabetes and hypertension.

Obesity plays a pivotal role in the pathophysiology of metabolic and cardiovascular disease (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). These disorders include impaired glucose tolerance, Type 2 diabetes, hypertension, and dyslipidemia. Obesity, defined as excessive storage of energy in the form of fat, has adverse effects on other diseases, such as certain cancers, which contribute to increased morbidity and mortality in our increasingly overweight society. If obesity is defined as a body mass index of 20% above the desirable index (approximately a body mass index of 27 kg/m), ~34 million adult Americans can be considered obese (12). Increasing related adiposity as a function of increasing age (14)(15)(16) also contributes to the increase in diabetes and hypertension with aging in Westernized, industrialized societies.

The cause of obesity is unknown, but abnormalities of leptin homeostasis have been proposed to increase the propensity to obesity (17). Leptin is a 16-kDa polypeptide hormone synthesized and released by the adipose tissue in proportion to the amount of triglyceride stores (17). Development of obesity in some rodent models is related to mutations in leptin or the leptin receptor. Furthermore, administration of leptin to obese rats lacking leptin normalizes body weight, metabolism, and the regulation of the hypothalamic-pituitary axis (17). However, most obese persons have no mutations in leptin or the leptin receptor. Indeed, they have increased leptin proportionate to their adiposity (17). Because the expected increase in leptin concentration would be expected to decrease appetite and increase thermogenesis, some obese persons may be resistant to their high endogenous leptin concentrations. Thus, the clinical utility of measuring serum leptin concentrations is unknown. Clinical trials are in progress to evaluate the effects of administration of exogenous leptin or leptin analogs in an attempt to overcome the leptin resistance.

The 1990 guidelines of recommended weights for adults published by the United States Department of Agriculture (18) suggest that a weight gain of no more than 7 kg between the ages of 20 and 35 years and older may be desirable. However, recent data from the Nurses Health Study (19) suggest that this concept is incorrect. This study began in 1977 and has examined in a longitudinal fashion the relationships between diet, exercise, use of hormones, and the development of a number of chronic illnesses among women. In this cohort, those who gained substantial weight after age 18 were at significantly increased risk of coronary heart disease (CHD)¹ (20), Type 2 diabetes mellitus (20)(21)(22), and total mortality (21), compared with women who remained within 5 pounds of their weight at age 18. The risk of weight gain for development of Type 2 diabetes was especially impressive. Over a 14-year follow-up of 114 824 women, the risk for development of diabetes increased monotonically with a body mass index >22 kg/m. In contrast, women who lost >5 kg from early adult life had a significantly reduced risk for diabetes. These results are also consistent with results in smaller numbers of males and females in other studies showing a relation between weight gain and risk for diabetes in adolescents (22) and adults (22)(23). In the latter study, men and women between the ages of 40 and 60 years had a similar associated risk for development of diabetes with increases in body weight after 18 years of age (23). On the basis of these and other recent observations, the more recent Department of Agriculture guidelines (24) place greater emphasis on avoiding weight gain and state, "Balance the food you eat with physical activity. Maintain or improve your weight". "Healthy weight ranges" for men and women are published in reference 24.

Visceral adiposity appears to be an especially strong risk factor for hypertension, dyslipidemia, CHD, and insulin resistance of Type 2 diabetes (24)(25)(26)(27)(28). Visceral fat is fat present in the omental and paraintestinal regions. Insulin resistance in persons with visceral obesity may relate in part to the metabolic characteristics of visceral fat cells, which when compared with peripheral fat cells, are more resistant to the metabolic effects of insulin and more sensitive to lipolytic hormones (29)(30). Indeed, increased release of free fatty acids into the portal system provides increased substrate for hepatic triglyceride synthesis and may impair first-pass metabolism of insulin. The insulin-resistant dyslipidemic state of visceral obesity is not typically associated with marked increases in plasma cholesterol and LDL-cholesterol concentrations (27). Techniques such as gradient gel electrophoresis and the measurement of plasma apolipoprotein (Apo) B concentrations have shown that the dyslipidemia characterizing visceral obesity is that of increased Apo B concentrations as well as the proportion of small dense LDL particles (27). These patients also typically display low concentrations of HDL-cholesterol and increased triglyceride concentrations in plasma.

The risk of CHD associated with the metabolic abnormalities of visceral obesity were recently described in a report from the Quebec Cardiovascular Study, a prospective study in which >2000 middle-aged men were followed over a period of 5 years. Two characteristic abnormalities of visceral obesity, fasting hyperinsulinemia and increased Apo B, were strong independent risk factors for CHD (31)(32). Concentrations of small, dense LDL-cholesterol are also increased in persons with central obesity (31)(32). The presence of small, dense LDL particles is associated with an approximately threefold increase in CHD risk; this risk is further increased in the presence of increased Apo B concentrations (10)(33) (Table 1 ). Visceral adipose tissue has greater lipolytic activity than subcutaneous adipose tissue (34)(35)(36)(37)(38). The consequent release of free fatty acids into the portal blood supply may contribute to abnormalities of lipoprotein metabolism, including the presence of increased small, dense LDL-cholesterol particles, lower concentrations of HDL, and hyperinsulinemia/insulin resistance (33)(34)(35)(36)(37)(38)(39), all of which are associated with increased propensity to CHD.

The hyperinsulinemia associated with visceral obesity (40)(41) appears to predispose persons to increased CHD and stroke (41)(42)(43)(44)(45)(46)(47)(48)(49). Four large prospective studies have shown that hyperinsulinemia is a predictor of CHD (31)(42)(43)(44)(45), with a few prospective reports not demonstrating such a relationship (40)(41). The greatest association of hyperinsulinemia with CHD has been found in Finland, in a population with a very high frequency of CHD (41). A recent report (31) of a prospective investigation of 2103 men from Quebec clearly showed that high fasting insulin concentrations are an independent predictor of CHD. This important study used an insulin assay without cross-reactivity with proinsulin, thus avoiding that confounding influence (31). Several recent studies have shown a relationship between carotid wall atherosclerotic lesions, angina, and insulin concentrations/resistance (48)(49)(50)(51)(52)(53)(54)(55). Thus, hyperinsulinemia does appear to be a predictor for the development of CHD and stroke.

Concentrations of plasminogen activator inhibitor (PAI) have been reported to be increased in obese persons, particularly those with visceral obesity (56). PAI-1 complexes with tissue-type plasminogen activator, eliminating its fibrinolytic activity (57)(58)(59)(60). The increased concentrations of PAI-1 appear to be related to hyperinsulinemia-associated obesity, particularly central obesity (31)(40)(41)(55)(56). A relative imbalance of the fibrinolytic factors may be associated with CHD. Increased concentrations of PAI-1 have been associated with an increased risk of thrombosis in animal and clinical studies (57)(58)(59)(60). In one clinical study, low tissue-type plasminogen activator activity and higher PAI-1 concentrations were observed in survivors of myocardial infarction compared with healthy age-matched controls (58). In another study, low tissue-type plasminogen activator activity and increased PAI-1 concentrations were the only hemostatic variables associated with recurrent myocardial infarction in a group of men with early coronary heart disease (59). Imbalance of the fibrinolytic proteins can also have pathogenic consequences within the vascular wall. In vascular tissue, plasmin activates matrix metalloproteinases, which are crucial in remodeling after vascular injury through degradation of collagen and other glycoproteins that accumulate in plaques. Several groups have reported increased PAI-1 in and around atherosclerotic plaques, which in turn would be expected to reduce vascular plasmin activation and, subsequently, metalloproteinase activity. This reduction in plasmin activation is also associated with reduced activation of transforming growth factor-ß, which is important in suppressing the proliferation and migration of smooth muscle cells that contribute to atherosclerotic lesions (60).

Other risk factors associated with obesity that may be reduced with weight reduction include increased blood pressure, fibrinogen, blood viscosity, and C-reactive proteins (61). Increases in the concentrations of these CHD risk factors appear to track with increased concentrations of insulin and triglycerides. All of these important risk factors have been demonstrated to be reduced by modest weight reduction (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75). Particularly in males, this is likely related primarily to the fact that initial weight loss is associated with a predominant reduction in visceral fat, the adipose tissue most strongly linked to these metabolic and hemodynamic CHD risk factors (61).

Various methodologies have been utilized to ascertain visceral adiposity, including imaging techniques such as computerized tomography and magnetic resonance imaging (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). These techniques are expensive and unavailable to many primary care providers. Thus, recently there have been a number of investigations of the utility of using simple anthropometric indexes as predictions of visceral adipose mass. The waist-to-hips ratio is the anthropometric variable that has been most widely utilized. The waist-to-hips ratio is, however, influenced by a number of factors other than regional adipose tissue distribution, such as frame size and skeletal muscle mass (76). It has been reported (76) that waist circumference is a better determinant of the absolute amount of visceral fat than the waist-to-hips ratio. This investigation also noted that waist circumference values of 1 meter in persons below 40 years of age and 90 cm among those between 40 and 60 years of age were associated with the metabolic abnormalities of visceral obesity and thus increased CHD risk (76).

Currently, there are potentially novel approaches to the prevention and treatment of obesity. It has recently been observed that leptin administration to rodents selectively decreases visceral adiposity and enhances insulin action (77). These observations suggest that this may be one of the promising strategies for approaching visceral obesity and the associated CHD risk factors. Similar to the observations for Type 2 diabetes, increases in indexes of obesity also relate strongly to increases in blood pressure (40). Furthermore, visceral adiposity is more closely associated with increases in blood pressure than is peripheral fat distribution (11)(40)(67)(68)(69)(70). This may be of special importance in certain subsegments of the US population, such as in African-American women (9)(10)(11)(67), where the prevalence of obesity is 40% (72). Declining levels of physical activity in our society likely contribute substantially to obesity, diabetes, and hypertension (9)(10)(11)(12)(13). This has considerable importance in formulation of future public health policy because overweight and physical inactivity are both preventable and reversible (11)(13)(73)(74)(75).

Acknowledgments

I wish to thank Paddy McGowan and Eleanor May for their fine work in preparing this manuscript.

Footnotes

¹ Nonstandard abbreviations: CHD, coronary heart disease; Apo, apolipoprotein; and PAI, plasminogen activator inhibitor.

References

1. Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, et al. Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest 1985;75:809-817.
2. Stevens J, Keil JE, Rust PF, Verdugo RR, Davis CE, Tyroler HA, et al. Body mass index and body girths as predictors of mortality in black and white women. Arch intern Med 1992;152:1257-1262. [Abstract/Free Full Text]
3. Després JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 1990;10:497-511. [Abstract/Free Full Text]
4. Everhart J, Knowler WC, Bennett PH. Incidence and risk factors for non-insulin dependent diabetes. In: National Diabetes Data Group. Diabetes in America. NIH Publication No. 85–1468. Bethesda, Maryland: US Department of Health and Human Services, 1985;IV:1–35..
5. Holbrook TL, Barrett-Connor E, Wingard DL. The association of lifetime weight and weight control patterns with diabetes among men and women in an adult community. Int J Obesity 1989;13:723-729. [Web of Science][Medline] [Order article via Infotrieve]
6. Bonham GS, Brock DB. The relationship of diabetes with race, sex, and obesity. Am J Clin Nutr 1985;41:776-783. [Abstract/Free Full Text]
7. Reaven GM. Bating Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-1607. [Abstract]
8. Haffner SM. Hyperinsulinemia as a possible etiology for the high prevalence of non-insulin dependent diabetes in Mexican Americans. Diabetes Metab 1987;13:337-344. [Web of Science]
9. Flack JM, Sowers JR. Epidemiologic and clinical aspects of insulin resistance and hyperinsulinemia. Am J Med 1991;91(Suppl 1A):11S-21S.[Medline] [Order article via Infotrieve]
10. Monolio TA, Savage PJ, Burke GL, Liu KA, Wagenknecht LE, Sidney S, et al. Association of fasting insulin with blood pressure and lipids in young adults. The CARDIA study. Arteriosclerosis 1990;10:430-436. [Abstract/Free Full Text]
11. Bakris GL, Weir MR, Sowers JR. Therapeutic challenges in the obese diabetic patient with hypertension. Am J Med 1996;100:335-465.
12. Caro JF. Clinical review 26: insulin resistance in obese and non-obese man. J Clin Endocrinol Metab 1991;73:691-695. [Abstract/Free Full Text]
13. Sowers JR, Farrow SL. Treatment of elderly hypertensive patients with diabetes, renal disease, and coronary heart disease. Am J Geriat Cardiol 1996;5:57-70. [Medline] [Order article via Infotrieve]
14. Busby MJ, Bellantoni MJ, Tobin JD, Muller DC, Kafonek SD, Blackman MR. Glucose tolerance in women: the effects of age, body composition, and sex hormones. J Am Geriat Soc 1992;40:497-502. [Web of Science][Medline] [Order article via Infotrieve]
15. Holbrook TL, Barret-Connor E, Wingard DL. The association of lifetime weight and weight control patterns with diabetes among men and women in an adult community. Int J Obesity 1989;13:723-729.
16. Coldritz GA, Willet WC, Rotsnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes in women. Ann Intern Med 1995;122:481-486. [Abstract/Free Full Text]
17. Caro JF, Sinha MK, Kolacznski JW, Zhang PL, Considine RV. Leptin. The tale of an obesity gene. Diabetes 1996;45:1455-1462. [Web of Science][Medline] [Order article via Infotrieve]
18. . US Department of Agriculture. Report of the crudeline advisory committee of the dietary guidelines for Americans, 1990 1990 US Government Printing Office Washington, DC. .
19. Coldritz GA, Munson JE, Hankinson SE. The Nurses Health Study: 20-year contribution to the understanding of health among women. J Women Health 1997;6:49-62. [Web of Science][Medline] [Order article via Infotrieve]
20. Willet WC, Manson JE, Stampler MJ, Colditz GA, Rosner B, Speizer FE, Hennekens CH. Weight, weight change, and coronary heart disease in women: risk within the "normal" weight range. JAMA 1995;273:461-466. [Abstract/Free Full Text]
21. Manson JE, Willet WC, Sampler MJ, Colditz GA, Hunter DJ, Hankinson SE, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-681. [Abstract/Free Full Text]
22. Bray GA. Obesity increases risk of diabetes. Int J Obesity 1992;16(Suppl E):513-517.
23. Haffner SM, Karhapää Mykk, änen L, Laasko M. Insulin resistance, body fat distribution, and sex hormones in men. Diabetes 1994;43:212-219. [Abstract]
24. . US Department of Agriculture. Report of the dietary guidelines advisory committee on the dietary guidelines for Americans, 1995 1995 US Department of Agriculture To the Secretary of Health and Human Services and the Secretary of Agriculture. Washington, DC. .
25. Pouliot MC, Després JP, Nadeau A, Moorjani S, Prud'homme D, Lupien PJ, et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 1992;41:826-834. [Abstract]
26. Spiegelman D, Israel RG, Bouchard C, Willet WC. Absolute fat mass, percent body fat, and body-fat distribution: which is the real determinant of blood pressure and serum glucose?. Am J Clin Nutr 1992;55:1033-1044. [Abstract/Free Full Text]
27. Tchernof A, Lamarche B, Prud'homme A. The dense LDL phenotype: association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men. Diabetes Care 1996;19:629-637. [Abstract]
28. Banerji MA, Lebowitz J, Chaiken RL, Gordon D, Kral J. Relationships of visceral adipose tissue and glucose disposal in independent of sex in black NIDDM subjects. Am J Physiol 1997;273:E425-E432. [Abstract/Free Full Text]
29. Tandia D, Krotkrewski Smith U. Importance of obesity for the metabolic abnormalities associated with an abdominal fat distribution. Metabolism 1989;38:572-576. [Web of Science][Medline] [Order article via Infotrieve]
30. Jensen M, Haymond M, Rizza R, Cryer P, Mules J. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Investig 1989;83:1168-1173.
31. Després JP, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-957. [Abstract/Free Full Text]
32. Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dayenais GR, et al. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five year follow-up of men in the Quebec Cardiovascular Study. Circulation 1996;94:273-278. [Abstract/Free Full Text]
33. Lamarche B, Tchernof A, Moorjani S, Cantin B, Bernard PM, Dagenurs GR, et al. Small dense low-density lipoprotein particles as a predictor of risks of ischemic heart disease. Circulation 1997;95:69-75. [Abstract/Free Full Text]
34. Roust LR, Jensen MD. Post prandial free fatty acids kinetics are abnormal in upper body obesity. Diabetes 1993;42:1567-1573. [Abstract]
35. Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol Rev 1994;74:761-811. [Free Full Text]
36. Hoffstedt J, Wahrenberg H, Thorne A, Lönnqvist F. The metabolic syndrome is related to beta 3-adrenoceptor sensitivity in visceral adipose tissue. Diabetologia 1996;39:838-844. [Web of Science][Medline] [Order article via Infotrieve]
37. Hoffstedt J, Arner P, Hellers G, Lönnqvist F. Variation in adrenergic regulation of lipolysis between omental and subcutaneous adipocytes from obese and non-obese men. J Lipid Res 1997;38:795-804. [Abstract]
38. Mauriège P, Prud'homme D, Lemieux S, Tremblay A, Deprés JP. Regional differences in adipose tissue lipolysis from lean and obese women: existence of postreceptor alterations. Am J Physiol 1995;269:E341-E350. [Abstract/Free Full Text]
39. Zamboni M, Rossiti L, Giaccar A. Relationship between visceral fat, steroid hormones and insulin sensitivity in premenopausal obese women. J Intern Med 1994;236:521-527. [Web of Science][Medline] [Order article via Infotrieve]
40. Sowers JR, Epstein M. Diabetes mellitus and hypertension: an update. Hypertension 1995;26:869-879. [Abstract/Free Full Text]
41. Sowers JR. Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension 1997;29:691-699. [Free Full Text]
42. Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two populations studies in Finland. Diabetes Care 1979;2:131-141. [Abstract]
43. Welborn TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference glucose and insulin concentrations. Diabetes Care 1979;2:154-160. [Abstract]
44. Ducimetiere P, Eschwege E, Papox L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin level to the incidence of myocardial infarction and coronary heart disease. Diabetologia 1980;19:205-210. [Web of Science][Medline] [Order article via Infotrieve]
45. Fontbonne A, Charles MA, Thibult N, Richard JL, Claude JR, Warnet JM, et al. Hyperinsulinemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia 1991;34:356-361. [Web of Science][Medline] [Order article via Infotrieve]
46. Welin L, Eriksson H, Larsson B, Ohlson L-O, Svärdsudd K, Tibblin G. Hyperinsulinemia is not a major coronary risk factor in elderly men: the study of men born in 1913. Diabetologia 1992;35:766-770. [Web of Science][Medline] [Order article via Infotrieve]
47. Haragreaves AD, Logan RL, Elton RA, Buchanan KD, Oliver MF, Riemersmaa RA. Glucose tolerance, plasma insulin, HDL cholesterol and obesity: 12-year follow-up and development of coronary heart disease in Edinburgh men. Atherosclerosis 1992;94:61-69. [Web of Science][Medline] [Order article via Infotrieve]
48. Ferrara LA, Mancini M, Celentano A, Galderisi M, Iannuzzi R, Marotta T, et al. Early changes of the arterial carotid wall in uncomplicated primary hypertensive patients. Arterioscler Thromb 1994;14:1290-1296. [Abstract/Free Full Text]
49. Folsom AR, Eckfeldt JH, Weitzman S, Ma J, Chambless LE, Barnes RW, et al. Atherosclerosis risk in communities (ARIC) study investigators: relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Stroke 1994;25:66-73. [Abstract]
50. Salomaa V, Riley W, Kark JD, Nardo C, Folsom AR. Non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes: the ARIC study. Circulation 1995;91:1432-1443. [Abstract/Free Full Text]
51. Agewall S, Fagerberg B, Attvall S, Wendelhag I, Urbanaavicius V, Wikstrand J. Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk. Stroke 1995;26:956-960. [Abstract/Free Full Text]
52. Shinozaki K, Suzuki M, Ikebuchi M, Takaki H, Hara Y, Tsushima M, et al. Insulin resistance associated with compensatory hyperinsulinemia as an independent risk factor for vasospastic angina. Circulation 1995;92:1749-1757. [Abstract/Free Full Text]
53. Shinozaki K, Naritomi H, Shimizu T, Suzuki M, Ikebuchi M, Sawada T, et al. Role of insulin resistance associated with compensatory hyperinsulinemia in ischemic stroke. Stroke 1996;27:37-43. [Abstract/Free Full Text]
54. Suzuki M, Shinozaki K, Kanazawa A, Hara Y, Hattori Y, Tsushima M, et al. Insulin resistance as an independent risk for carotid wall thickening. Hypertension 1996;28:593-598. [Abstract/Free Full Text]
55. Walsh MF, Dominguez LJ, Sowers JR. Metabolic abnormalities in cardiac ischemia. Cardiol Clin 1995;13:529-538. [Medline] [Order article via Infotrieve]
56. Vague P, Gauhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, et al. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metab Clin Exp 1986;35:250-253.
57. Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 1990;346:74-76. [Medline] [Order article via Infotrieve]
58. Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of a tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985;313:1557-1563. [Abstract]
59. Hamsten A, Walldius G, Szamosi A, Blombäck M, de Faire U, Dahlen G, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987;2:3-9. [Web of Science][Medline] [Order article via Infotrieve]
60. Lupu F, Heom DA, Bachmann F, Hurni M, Kakkar VV, Kruithof ER. Plasminogen activator expression in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1995;15:1444-1445. [Abstract/Free Full Text]
61. Van Gaal LF, Wanters T, DeLeeuw IH. The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obesity 1997;21:S5-S9. [Web of Science]
62. Sowers JR, Whitfield L, Beck F, Catania RA, Tuck ML, Dornfeld L, Maxwell M, et al. Role of enhanced sympathetic nervous system activity and reduced Na⁺K⁺ adenosine triphosphate activity in maintenance of elevated blood pressure in obesity: effects of weight loss. Clin Sci 1982;63:121-124. [Medline] [Order article via Infotrieve]
63. Landsberg L. Obesity and hypertension experimental data. J Hypertens 1992;10(Suppl 7):S195-S201.
64. Istfan NW, Plaisted CS, Bistrian BR, Blackburn GL. Insulin resistance versus insulin secretion in the hypertension of obesity. Hypertension 1992;19:385-392. [Abstract/Free Full Text]
65. Jacobs DB, Sowers JR, Hmeidan A, Niyogi T, Simpson L, Standley PR. Effects of weight reduction and cellular cation metabolism and vascular resistance. Hypertension 1993;21:308-314. [Abstract/Free Full Text]
66. Sinagru D, Greco D, Scarpitta AM, Bonaventura V. Blood pressure, insulin secretion and resistance in non-hypertensive and hypertensive obese female subjects. Int J Obesity 1995;19:610-613. [Web of Science]
67. Stevens J, Keil JE, Rust PF, Verdugo RR, Davis CE, Tyroler HA. Body mass index and body girths as predictors of mortality in black and white women. Arch Intern Med 1992;152:1257-1262.
68. Dowse GK, Zimmet PZ, Gareebou H, George K, Alberti MM, Tuomilehto J. Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians. Diabetes Care 1991;14:271-282. [Abstract]
69. Iso H, Kiyama M, Naito Y, Sato S. The relation of body fat distribution and body mass index with hemoglobin A₁C, blood pressure and blood lipids in urban Japanese men. Int J Epidemiol 1991;20:88-94. [Abstract/Free Full Text]
70. Hodge AM, Dowse GK, Zimmet PZ. Association of body mass index and waist-hip circumference ratio with cardiovascular disease risk factors in Micronesian Nauruans. Int J Obesity 1993;17:399-407. [Web of Science]
71. . National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group report on hypertension in the elderly. Hypertension 1994;23:275-285. [Abstract/Free Full Text]
72. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination surveys. 1960 to 1991. JAMA 1994;272:205-211. [Abstract/Free Full Text]
73. Sowers JR. Modest weight gain and the development of diabetes: another perspective. Ann Intern Med 1995;122:548-549. [Free Full Text]
74. Tuck ML, Sowers JR, 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;298:1-6.
75. Barnard RJ, Jung T, Inkeles SB. Diet and exercise in the treatment of NIDDM: the need for early emphasis. Diabetes Care 1994;17:1469-1472. [Abstract]
76. Lemieux S, Prud'homme D, Bouchard C, Tremblay A, Després JP. A single threshold value of waist girth subjects with excess visceral adipose tissue. Am J Clin Nutr 1996;64:685-693. [Abstract/Free Full Text]
77. Barzilai N, Wang J, Massilon D, Vaguin P, Hawkins M, Rossiti L. Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Investig 1997;100:3105-3110. [Web of Science][Medline] [Order article via Infotrieve]