Published online before print December 27, 2005, doi: 10.1161/CIRCULATIONAHA.106.171016
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(Circulation. 2006;113:898-918.)
© 2006 American Heart Association, Inc.
AHA Scientific Statement |
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
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Abstract |
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Top
Abstract
IntroductionObesity is becoming a global epidemic in both children and adults. It is associated with numerous comorbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, obesity is an independent risk factor for CVD, and CVD risks have also been documented in obese children. Obesity is associated with an increased risk of morbidity and mortality as well as reduced life expectancy. Health service use and medical costs associated with obesity and related diseases have risen dramatically and are expected to continue to rise. Besides an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts, even in the absence of comorbidities. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, in addition to as-yet-unrecognized mechanisms. On the whole, overweight and obesity predispose to or are associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death because of their impact on the cardiovascular system. The pathophysiology of these entities that are linked to obesity will be discussed. However, the cardiovascular clinical evaluation of obese patients may be limited because of the morphology of the individual. In this statement, we review the available evidence of the impact of obesity on CVD with emphasis on the evaluation of cardiac structure and function in obese patients and the effect of weight loss on the cardiovascular system.
Key Words: AHA Scientific Statements • obesity • cardiovascular diseases • heart diseases • diagnosis
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Introduction |
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Obesity is becoming a global epidemic,1,2 and in the past 10 years in the United States, dramatic increases in obesity have occurred in both children and adults.3–5 Historically, the Metropolitan Life Insurance Company data that express body fatness as percent ideal body weight have been used,6 but currently overweight and obesity are classified by body mass index (BMI). BMI (weight in kilograms/height2 in meters) is frequently used as a surrogate measure of fatness in children and adults. In adults, overweight is defined as a BMI of 25.0 to 29.9 kg/m2; obesity is defined as a BMI
30.0 kg/m2. Table 1 shows the classification developed by a National Heart, Lung, and Blood Institute task force, along with the associated disease risk with increasing BMI.7 Through the use of the BMI, the epidemic of obesity that began in the 1980s has been tracked through the end of the century.4,8 The original alarm was sounded in 1994 by the National Center for Health Statistics when they reported their data from the first 3 years of the National Health and Nutrition Examination Survey (NHANES).9 The authors observed that from 1988–1994 (NHANES III) to NHANES 1999–2000, the prevalence of overweight in adults increased from 55.9% to 64.5%. During that same period, the prevalence of obesity increased from 22.9% to 30.5%.4,5,10 This sudden, unanticipated jump in the prevalence of obesity led the American Heart Association (AHA) to call for action to curb the consequences of this epidemic.11,12 More recently, the AHA has addressed and reviewed a variety of weight loss approaches for the management and treatment of obesity.13 Beyond an unfavorable risk factor profile, overweight and obesity also affect heart structure and function. Moreover, the cardiovascular clinical evaluation of obese patients may be limited because of the morphology of the individual. This statement reviews the available evidence of the impact of obesity on cardiovascular disease (CVD), with emphasis on the evaluation of cardiac structure and function in obese patients and the effect of weight loss on the cardiovascular system.
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Obesity as a Metabolic/Genetic CVD Risk Factor |
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Over the past 2 decades, an explosive increase in the number of people with the metabolic syndrome (MetS) has taken place all around the globe. To better characterize the syndrome, several definitions of the MetS have been published, and the issue of the definition of the MetS has been reviewed lately.14 However, the uncertainty about its pathogenesis has brought some doubt with regard to whether the MetS is a syndrome or an independent CVD risk factor.15 Nevertheless, MetS may be associated with the global epidemic of obesity and diabetes—reported in Zimmet et al as "diabesity."16 Given the elevated risk of not only diabetes but also CVD from the MetS,17 strategies to stop the emerging global epidemic of obesity are urgently needed.16 The MetS can present in a variety of ways aligned to the various components that constitute the syndrome.18 Of note, abdominal obesity is a risk factor for CVD worldwide.19,20 The estimated years of life lost as the result of obesity differ among races and between genders, but it was estimated that the optimal BMI for adults age 18 to 85 years is 23 to 25 for whites and 23 to 30 for blacks.21 The MetS is associated with an increased risk of both diabetes17 and CVD.22–25 In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study involving European men and women, nondiabetic persons with the MetS had an increased risk of death from all causes as well as from CVD.26 The overall hazard ratios for all-cause and CVD mortality in persons with the MetS as compared with persons without it were 1.44 and 2.26 in men and 1.38 and 2.78 in women after adjustment for age, blood cholesterol levels, and smoking. In 2 other European prospective studies,22,23 the presence of the MetS predicted increased CVD and coronary heart disease (CHD) mortality rates. Again, this is not unexpected, given that the MetS comprises established CVD risk factors. It was suggested that the life-shortening effect of obesity could rise as the obese who are now at younger ages carry their elevated risk of death into middle and older ages.27
The epidemic of obesity is occurring on genetic backgrounds that have not changed, but it is nonetheless clear that genetics plays an important role in the development of obesity.28 From the time of the early twin and adoption studies >10 years ago, large groups of individuals have been evaluated for genetic defects related to the development of obesity.29,30 These genetic defects can be divided into 2 groups: the rare genes that produce significant obesity, and a group of more common genes that underlie the propensity to develop obesity—the so-called "susceptibility" genes.28 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.31,32 Recent research has identified >41 sites on the genome as possible links to the development of obesity in a favorable environment.28 It is important to assess the gene–environment obesity relation because the prevalence of obesity, especially in children, is likely to continue to rise.
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Obesity and Associated Comorbidities |
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Obesity is associated with numerous comorbidities such as CVD, type 2 diabetes, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD,33,34 and CVD risks have been documented in obese children.8,35 Indeed, a relationship exists between BMI in adolescence and all-cause mortality.3 After a follow-up of 31.5 years, with those with a BMI between the 25th and 75th percentiles used as control subjects, it was reported that a BMI above the 95th percentile in adolescence predicted adult mortality rates in both male (80% increment) and female (
100% increment) patients. A 30% increase in all-cause mortality was also seen in female and male subjects when baseline BMI was between the 85th and 95th percentiles.3 Another study, after 55 years of follow-up, reported an excess mortality rate among male but not female subjects who were overweight (BMI >75th percentile in the US reference population) in adolescence as compared with those who were lean (BMI 25th to 49th percentiles). The observed increased risk of death was independent of adult BMI.36 Thus, obesity is associated with an increased risk of morbidity and mortality and is associated with reduced life expectancy.21,27,37–41 Besides an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts,42 even in the absence of comorbidities. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, as well as through yet-unrecognized mechanisms. As a whole, overweight/obesity predisposes or is associated with numerous cardiac complications such as CHD, heart failure, and sudden death through its impact on the cardiovascular system. The pathophysiology of these entities linked to obesity will be discussed in the following sections.
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Cardiovascular Impact of Increased Adipose Tissue Mass |
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Adipose Tissue Circulation
It has long been recognized that an extensive capillary network surrounds adipose tissue.43 Adipocytes are located close to vessels with the highest permeability, the lowest hydrostatic pressure, and the shortest distance for transport of molecules to and from the adipocytes.44,45 Resting blood flow is usually 2 to 3 mL/min per 100 g of adipose tissue46,47 and can increase
10-fold. This increment is still lower (20 mL/min per 100 g) than that seen in skeletal muscle (50 to 75 mL/min per 100 g).48 Adipose tissue blood flow increases after meal intake,49 but this modulation varies and may be decreased in patients with the features of the obesity-related MetS.50,51
Also, adipose tissue comprises a substantial proportion of total body weight. Therefore, a large quantity of fluid is present in the interstitial space of adipose tissue, as the interstitial space is 10% of the tissue wet weight.52 Excess fluid in this compartment may have important repercussions in obese individuals with heart failure if this extra volume is redistributed into the circulation; however, modulation of blood flow through adipose tissue typically prevents this from occurring. This is because blood flow in adipose tissue is regulated by ß1-receptors that mediate vasodilation, in contrast to those of skeletal muscle, which are mainly ß2.45 As a consequence of this decrease in blood flow in adipose tissue, the fluid present in the interstitial compartment is not readily accessible. Although cardiac output increases with total fat mass, the perfusion per unit of adipose tissue actually decreases with increasing obesity, that is, from 2.36 mL/min per 100 g to 1.53 mL/min per 100 g of adipose tissue (35%) in patients who have 15% to 26% body fat compared with those with >36% body fat.47 Accordingly, the increase in systemic blood flow encountered in obesity cannot be explained solely by increased requirements caused by adipose tissue perfusion because the enlarged vascular bed of adipose tissue is less vascularized than other tissue. Probably, the concomitant increase in lean body mass in these individuals accounts for some of the increased cardiac output.53 Indeed, it has been reported that stroke volume, cardiac output, and left ventricular mass may be more related to fat-free mass than to fat mass.53,54
The adipose tissue is not simply a passive storehouse for fat but an endocrine organ that is capable of synthesizing and releasing into the bloodstream an important variety of peptides and nonpeptide compounds that may play a role in cardiovascular homeostasis. Although this is not an extensive enumeration, adipose tissue is a significant source of tumor necrosis factor-
(TNF-), interleukin-6 (IL-6), plasminogen activator inhibitor-1, resistin, lipoprotein lipase, acylation stimulating protein, cholesteryl-ester transfer protein, retinal binding protein, estrogens (through P450 aromatase activity), leptin, angiotensinogen, adiponectin, insulin-like growth factor-I (IGF-I), insulin-binding protein 3 (IGFBP3), and monobutyrin.55–59 Of clinical consideration, circulating concentrations of plasminogen activator inhibitor-1, angiotensin II, C-reactive protein (CRP), fibrinogen, and TNF- are all related to BMI.60,61 It has been estimated that in vivo, 30% of the total circulating concentrations of IL-6 originate from adipose tissue.60,62 This is of importance because IL-6 modulates CRP production in the liver, and CRP may be a marker of a chronic inflammatory state that can trigger acute coronary syndrome.63
Hemodynamic Repercussion of Obesity
Obesity produces an increment in total blood volume and cardiac output that is caused in part by the increased metabolic demand induced by excess body weight.64,65 Thus, at any given level of activity, the cardiac workload is greater for obese subjects.66,67 Obese subjects have higher cardiac output and a lower total peripheral resistance than do lean individuals. The increased cardiac output is attributable mostly to increased stroke volume because heart rate increases little if at all.68,69 Also, in obesity, the Frank-Starling curve is shifted to the left because of incremental increases in left ventricular filling pressure and volume, which over time may produce chamber dilation. Ventricular chamber dilation may then lead to increased wall stress, which predisposes to an increase in myocardial mass and ultimately to left ventricular hypertrophy, characteristically of the eccentric type.70,71 Left atrial enlargement may also occur in normotensive obese individuals but typically in the setting of increased left ventricular mass. Left atrial enlargement may not be mediated solely through left ventricular diastolic dysfunction impairment but may simply reflect a physiological adaptation to the expanded blood volume.72 As a consequence, left atrial dilation may mediate the excess risk of atrial fibrillation associated with obesity.73 However, left ventricular hypertrophy (LVH) in long-standing obesity and/or the effects of concomitant hypertension may also be contributing factors to left atrial enlargement.
Weight loss through diet and exercise is recommended in the management of obesity,13 but it is important to recognize that obesity is associated with persistence of elevated cardiac filling pressures during exercise.74,75 Increased cardiac output during exercise is typically accompanied by an increase in left ventricular filling pressure, often exceeding 20 mm Hg. Therefore, the average left ventricular filling pressure is often within the upper limits of normal at rest but increases disproportionately with increased venous return during exercise.68 This is consistent with a high-pressure system, and, accordingly, obese patients may demonstrate higher right heart filling pressures, systolic pressure, cardiac output, and pulmonary vascular resistance index.65 The latter may reflect intrinsic pulmonary disease, abnormal left ventricular function, or undiagnosed causes of pulmonary hypertension such as sleep apnea/hypoventilation or recurrent pulmonary thromboembolism. With increased venous return, small increments of central blood volume are associated with a significant increase in left ventricular end-diastolic pressure. A decrease in central blood volume accompanies weight reduction, and, when present, relief of edema and dyspnea may accompany this improvement.68
Effects on Ventricular Function
Eccentric LVH, which is commonly present in morbidly obese patients (BMI40 kg/m2), is often associated with left ventricular diastolic dysfunction. Moreover, as with left ventricular mass, longer durations of obesity are associated with poorer left ventricular systolic function and greater impairment of left ventricular diastolic function.76 Because of the presence of nonspecific symptoms, the evaluation of the presence of left ventricular diastolic dysfunction is clinically important in obese subjects.34,77–79 Age and cardiac hypertrophy of the concentric80,81 or, more commonly, the eccentric type82,83 predispose to left ventricular systolic dysfunction. Although postmortem studies have demonstrated a relationship between heart weight and body weight,80,84 obese patients without concomitant comorbidities may be afflicted only by diastolic dysfunction and hyperkinetic systole without LVH when indexed by fat-free mass.83 In humans and most animal models, the development of obesity leads not only to increased fat depots in classic adipose tissue locations but also to significant lipid deposits in other organs. With fat gain, lipid deposition can impair tissue and organ function in 2 possible ways: (1) The size of fat pads around key organs may increase substantially, modifying organ function either by simple physical compression or because periorgan fat cells may secrete various locally acting molecules, and (2) lipid accumulation can occur in nonadipose cells and may lead to cell dysfunction or cell death, a phenomenon known as lipotoxicity.85–87 Abnormal cellular adaptations may unfavorably affect the cardiac muscle, which is one of the several mechanisms leading to cardiomyopathy.
Cardiomyopathy of Obesity (Adipositas Cordis)
Obesity cardiomyopathy was recognized as early as 1818.88 The case described by Cheyne88 is of historic interest, not only because it is a carefully recorded documentation of a fatty heart but because it was the first reported case of Cheyne-Stokes respiration. Subsequently, other reports of excessive epicardial fat and fatty infiltration of the myocardium in the hearts of obese subjects were published that related the anatomic change to cardiac dysfunction.84,89 Initially, the fatty heart probably is not an infiltrative process but is a metaplastic phenomenon.90 Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.91 It may represent an adaptative substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment. Cords of cells can gradually accumulate fat between muscle fibers or cause myocyte degeneration, resulting in cardiac conduction defects.92,93 These cords of fat cells may also emanate from epicardial fat.90 When the right ventricle is involved, the sinus node musculature, the atrioventricular node, the right bundle branch,92 and, ultimately, the entire myocardium of the atrioventricular region might be replaced by fat.93 Occasionally, a pattern of restrictive cardiomyopathy develops.94,95 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.94 An alternative explanation could be, as discussed previously, the lipotoxicity of the myocardium induced by free fatty acids, which can cause apoptosis of lipid-laden cells such as cardiomyocytes.96
Thus, through different mechanisms (increased total blood volume, increased cardiac output, LVH, 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,67,77,97 it may be difficult to clinically assess an obese individual because of several limitations inherent to the subject’s morphology.
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Clinical and Laboratory Assessment of Obese Individuals |
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History and Physical Examination
The physical examination and ECG often underestimate the presence and extent of cardiac dysfunction in obese patients. Cardiovascular manifestations likely occur on a continuum from the overweight to the morbidly obese individuals because symptoms and signs of obesity cardiomyopathy occur mainly in patients with a relative weight
175% or a BMI 40 kg/m2.64 On physical examination, jugular venous distention and hepatojugular reflux may not be seen, and heart sounds are usually distant. However, dorsal hand veins, if visible, can estimate central venous pressure. The hand is lowered beneath the sternal angle until the dorsal veins are distended. The arm is then gradually and passively raised while the dorsal veins are observed. Normally, the dorsal hand veins empty at the level of the sternal angle when the patient’s trunk is 30° to 45° above the horizontal. Although this bedside technique remains a crude evaluation with several limitations, persistent distention is recorded as the vertical distance above the angle of Louis.98 In the very obese patient, symptoms of heart disease may remain nonspecific, but the clinician should carefully search for the presence of cor pulmonale. In the majority of individuals, the splitting of the S2 is most often heard at the second or third left interspace parasternally, but in obese patients, the split S2 is either inaudible or very poorly defined in the second interspace and is often best heard at the first left interspace.99 An electronic stethoscope may be helpful. This is of importance because pulmonary artery systolic pressure has been reported to be above the suggested normal limit (
30 mm Hg) in 51% of obese patients,100 and for each increase in BMI, the pulmonary artery systolic pressure is increased by 0.1 to 0.4 mm Hg.100
Electrocardiogram
Like physical evaluation, the ECG is influenced by morphological changes induced by obesity, such as (1) displacement of the heart by an elevated diaphragm in the supine position, (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.
Several changes in the ECG occur with increasing obesity (Table 2). In addition to low QRS voltage and leftward trend in the axis, other frequent alterations seen are nonspecific flattening of the T wave in the inferolateral leads (attributed to the horizontal displacement of the heart) and voltage criteria for left atrial abnormality.101–103 More frequent ST-segment depression is seen in overweight patients with CHD.104 Weight loss induces a rightward shift of the QRS axis,105,106 but conduction intervals (duration of the P wave, QRS complex, and the PQ interval) are not affected by weight loss.106 An increased incidence of false-positive criteria for inferior myocardial infarction has been reported in both obese individuals and in women in the final trimester of pregnancy. This is presumably because of diaphragmatic elevation.107
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Left ventricular hypertrophy is strongly associated with cardiac morbidity and mortality.108 Multiple ECG criteria for LVH are present more regularly in morbidly obese than in lean individuals but less frequently than might be expected on the basis of the high prevalence of echocardiographic LVH in such patients.101 Therefore, LVH is probably underdiagnosed by usual electrocardiographic criteria in morbidly obese individuals. A low frequency of LVH by voltage criteria in morbid obesity is encountered where LVH was demonstrated in two thirds of the obese subjects by echocardiography.101,109,110 As left ventricular mass increases, electrical forces usually become more posteriorly oriented, and the S wave in lead V3 may be the most representative voltage for evaluating posterior forces. With LVH, the heart is oriented more horizontally in the mediastinum, which may explain the usefulness of the R wave in AVL. In obesity, the heart is shifted horizontally, presumably from the restricted diaphragmatic expansion caused by the abdominal pannus. Thus, it was proposed that for men at all ages, LVH is present by QRS voltage alone when the amplitudes of the R wave in lead AVL and the S wave in lead V3 are >35 mm. For women at all ages, the same criteria were set at >25 mm.111 When ECG voltage criteria were compared with left ventricular mass estimated by echocardiography, a sensitivity of 49%, specificity of 93%, and overall accuracy of 76% were revealed. These percentages are higher than most widely used criteria (Romhilt-Estes point score and Sokolow-Lyon voltage). Therefore, Sokolow-Lyon voltage should be replaced by the Cornell voltage criteria, which appear to be less influenced by the presence of obesity.112
Although ECG parameters in obese patients should be expected to change after weight loss, the impact of weight loss in obese patients on the QRS voltage is not consistent; studies report a decrease,113–115 no change,116 or an increase in the QRS amplitude.102,105,106 With weight loss, a decreased amount of fat mass may counterbalance a true decrease in left ventricular mass, and a low QRS voltage could be secondary to myocardial atrophy.115,117,118 Thus, these opposite vectors may negate the resultant QRS amplitudes.
Echocardiography
In times past, the cardiac status of obese individuals was difficult to assess, and obesity-induced cardiac abnormalities were found only after death.80,84,88,90,103,119–123 Even since the development of echocardiography, transthoracic echocardiography can be technically difficult in obese patients.124,125 Differentiation between subepicardial adipose tissue and pericardial effusion is often difficult in obese patients.125,126 Epicardial adipose tissue is known to be a common cause of false-positive effusion (pseudopericardial effusion), and this adipose tissue depot may cause an underestimation of the amount of pericardial fluid.121,127 Adipose tissue can also be found within the heart—for example, in the interatrial septum. From necropsy descriptions, the definition of the lipomatous hypertrophy of the interatrial septum corresponds to a maximal transverse dimension of interatrial fat >20 mm.128,129 Although numerous indices of left ventricular diastolic filling are derived from echocardiography or cardiac Doppler evaluation, the increased intravascular volume in obesity may mask the Doppler-derived abnormalities of diastolic filling. Pulmonary venous Doppler evaluation may be used, but if not technically accessible, transmitral Doppler image may properly evaluate the presence of left ventricular diastolic dysfunction.130,131 Tissue Doppler has also been used to document diastolic dysfunction in obesity.132 To evaluate left ventricular mass in obese subjects, it has been suggested that indexing left ventricular mass according to height2.13 or height2.7 may be more appropriate than normalization for body surface area, or even for height.133,134 Another potential way to normalize the left ventricular mass is with lean body mass.135,136 Interestingly, after indexing by lean body mass, there were no gender differences on left ventricular mass, and the relative effects of adiposity and blood pressure on left ventricular mass were of similar magnitude.136 This finding was underscored recently by the results of the Strong Heart Study cohort, which showed that stroke volume and cardiac output are more strongly related to fat-free mass than other variables in both normal-weight and overweight individuals.53
Thus, obesity is associated with changes in the ECG that may affect the diagnosis of LVH or even CAD. Undoubtedly, the adiposity status has an impact on the heart size and function, but the optimal indexing criteria to define LVH after an echocardiographic study in obese individuals remain to be refined and confirmed. The next section will discuss comorbidities associated with obesity, with emphasis on the pathophysiology and the effect of weight loss.
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Vascular Disease |
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Venous Insufficiency
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.137,138 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 because of venous valvular incompetence. As for other causes of leg edema, the risk of the severe and sustained lower-extremity venous stasis disease seen 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 a large majority of patients.139
Venous Thrombosis and Pulmonary Embolus
The incidence of venous thromboembolism in the upper tertile of BMI was 2.42 times that in the lowest BMI tertile,140 and waist circumference >100 cm in men was also related to venous thromboembolism.141 Obesity also has been associated with an increased risk of pulmonary embolism in women,142 but this is less clear for men.141 Also, in an autopsy study, morbid obesity was an independent risk factor for death from pulmonary embolism after the exclusion of established clinical, environmental, and molecular risk factors.143,144
Endothelial Function
Obesity is associated with abnormal endothelial function.145 It is often inferred that the reduction in endothelial function is the result of a decrease in nitric oxide (NO). Decreased NO in obesity may be related to an increase in oxidative stress146 or may result from proinflammatory cytokines. In the Framingham Heart Study, BMI was highly associated with systemic oxidative stress, as determined by creatinine-indexed urinary 8-epi-PGF2 levels.147 A decrease in the function of NO would result in vasoconstriction and an increase in vascular resistance that may predispose to CVD risk factors such as hypertension.
Hypertension
The majority of patients with high blood pressure are overweight.148 Hypertension is about 6 times more frequent in obese subjects than in lean men and women.148 Not only is hypertension more frequent in obese subjects than in normal-weight control subjects, but also weight gain in young people is a potent risk factor for subsequent development of hypertension. A 10-kg higher body weight is associated with a 3.0-mm Hg higher systolic and a 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.7 However, results from NHANES III reported more specific estimates for the prevalence of high blood pressure per age group and BMI group.149 Among men, the prevalence of high blood pressure increased progressively with increasing BMI, from 15% at a BMI of <25 kg/m2 to 42% at a BMI of 30 kg/m2. Women showed a pattern similar to that of men; prevalence of hypertension being 15% at a BMI of <25 kg/m2 to 38% at a BMI of 30 kg/m2.149 The trend of higher prevalence of high blood pressure with increasing BMI was similar for white, black, and Mexican Americans of both genders, and the age-adjusted rates were highest among blacks at every level of BMI.149 It is well recognized that technical difficulties exist in the indirect measurement of blood pressure in the obese patient that may result in an overestimation of the level of blood pressure.150–152 Nevertheless, obesity is strongly associated with higher-than-optimal blood pressure.153,154 This increase in blood pressure is greatest when the obesity is of abdominal distribution.151,155–158 Factors to be considered in linking obesity to an increase in blood pressure are related to changes in cardiac output and peripheral vascular resistance, because BP=COxSVR, where BP is blood pressure, CO is cardiac output, and SVR is systemic vascular resistance. These factors include (1) direct effects of obesity on hemodynamics and (2) mechanisms linking obesity and an increase in peripheral vascular resistance: endothelial dysfunction, insulin resistance, sympathetic nervous system, substances released from adipocytes (IL-6, TNF-, and so forth), and sleep apnea.
Obesity per se is associated with alterations in hemodynamics.159 An increase in oxygen demand produced by excess adipose tissue (1.5 mL/kg per minute) requires an increase in cardiac output. Also, a parallel increase occurs in blood volume. Thus, obese individuals have an increase in blood volume, stroke volume, and cardiac output. This high-output state is associated with a reduction in peripheral vascular resistance in individuals with a normal blood pressure, as would be predicted from the Poiseuille formula: R=
P/F=(8/
)x(
)x(l/r4), where R is resistance, 8/ is a numerical factor, is blood viscosity, and l/r4 is a geometric factor that includes vessel characteristics. Because of the marked influence of the geometric factor (to the fourth power) in the equation, resistance is decreased. However, obese persons with a greater-than-optimal increase in blood pressure (ie, hypertension) have a peripheral vascular resistance that is either inappropriately "normal" or increased. Therefore, although an increase in cardiac output may add to the increase in blood pressure, in the obese individual, an abnormal increase in blood pressure is primarily dependent on an increase in peripheral vascular resistance.
Factors Leading to an Increase in Peripheral Vascular Resistance in Obesity Associated With Hypertension
The MetS (cardiovascular dysmetabolic syndrome; metabolic syndrome X) links hypertension with an increase in visceral fat.157,160–162 Insulin resistance has been proposed as a common mechanism linking the other components of the MetS, but racial differences exist in the relation between blood pressure and insulin resistance.163–165 Years ago, in the MetS, the prevalence of hypertension (blood pressure >130/85 mm Hg) was reported to be 80.1% for men and 40.7% for women.166 More recently, racial differences between genders in terms of MetS-associated high blood pressure were reported. Indeed, high blood pressure prevalence may vary from 3.9% in women to 17.1% in men age 20 to 34 years to 70.3% in women and 80.7% in men age 65 years.165 Obviously, if lower levels of blood pressure were considered optimal, the percentage of individuals with hypertension would be almost universal for men.167
One potential link between insulin resistance and an increase in blood pressure is the sympathetic nervous system.166 Overactivity of the sympathetic nervous system is supported by data from the Normotensive Aging Study showing that urinary norepinephrine increases with BMI, abdominal girth, and insulin-glucose levels.166 The role of insulin, however, is not supported by observations that patients with insulinomas are not hypertensive168 and that chronic intrarenal hyperinsulinemia does not cause hypertension.169 It was recently suggested that the documented association between obesity, fasting insulin, insulin sensitivity, and blood pressure may be explained by phenomena related to the concomitant variation in the amount of abdominal fat, as estimated by waist circumference.157
The association of obesity with a "systemic inflammatory state" may provide one other mechanism for an increase in blood pressure. A strong correlation exists between obesity and IL-6 and CRP levels.170 IL-6 is a proinflammatory cytokine that, among many other things, stimulates the production of CRP from the liver. Thus, obesity is somewhat similar to a low-grade systemic inflammation. Low-grade inflammation may play a role in increasing blood pressure.171 Increases in systolic and diastolic blood pressures, pulse pressure, and mean arterial pressure were significantly associated with levels of IL-6, whereas systolic blood pressure, pulse pressure, and mean arterial pressure were associated with levels of soluble intercellular adhesion molecule-1. Elevated plasma IL-6 levels were significantly associated with systolic and diastolic blood pressures in women, whereas in men, IL-6 was associated with fasting insulin and fasting insulin resistance index.171 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 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.172–174 Of note, after the weight loss has ceased, the persistent effect of weight loss on blood pressure may not always be encountered.175,176
The physician who evaluates a referred patient for hypertension should be very concerned about obese patients who admit habitual snoring, nocturnal gasping or choking, witnessed episodes of apnea, and daytime sleepiness and should consider sleep-disordered breathing.177–179
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Sleep Apnea |
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Numerous respiratory complications are associated with obesity. 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 classic cause of alveolar hypoventilation. Historically, the obesity-hypoventilation syndrome has been described as the "pickwickian" syndrome, and obstructive apnea was observed first in patients with severe obesity. Accordingly, obesity could represent a major cause of respiratory insufficiency and pulmonary hypertension in patients with obstructive sleep apnea. Sleep apnea is defined as repeated episodes of obstructive apnea and hypopnea during sleep, together with daytime sleepiness or altered cardiopulmonary function.180 The prevalence of sleep-disordered breathing and sleep disturbances rises dramatically in obese subjects,181 and obesity is by far the most important modifiable risk factor for sleep-disordered breathing.178,179 It is estimated that 40 million Americans have sleep disorders and that the vast majority of these patients remain undiagnosed.178,179 Despite careful screening by history and physical examination, sleep apnea is revealed only by polysomnography in a significant number of patients.182 Although some clinical presenting features could be useful as screening tools to diagnose sleep apnea, a high index of suspicion is needed by clinicians because the diagnostic accuracy may be low.183 The association of sleep-disordered breathing and sleep apnea with hypertension was studied in 6132 subjects over 40 years of age.184 Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing severity of sleep-disordered breathing. It was considered that obesity might be a confounding factor, given the strong association of obesity with sleep apnea. However, sleep apnea might be one of the intermediary mechanisms by which overweight is causally related to hypertension. Interestingly, sleep apnea is associated with increased levels of CRP. Thus, obesity may influence many processes that are linked—for example, sleep apnea, hypertension, and atherosclerosis.185 Although a link exists between sleep apnea and systemic hypertension, the association of obesity with both disorders confounds the relation.
It is important to remember, however, that the clinical and electrocardiographic signs of cor pulmonale appear later than those of pulmonary hypertension assessed by right heart catheterization. From a cardiology viewpoint, patients with sleep apnea have an increased risk of diurnal hypertension, nocturnal dysrhythmias, pulmonary hypertension, right and left ventricular failure, myocardial infarction, and stroke, as well as increased mortality rates.186 Numerous treatments are available for sleep apnea, but weight loss in obese patients should always be advocated.180
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Pulmonary Hypertension |
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The prevalence of pulmonary hypertension in subjects with obstructive sleep apnea is 15% to 20%, and pulmonary hypertension is rarely observed in the absence of daytime hypoxemia.187,188 According to Kessler et al,187 the gravity of pulmonary hypertension is generally mild to moderate (pulmonary artery pressure ranging between 20 and 35 mm Hg) and does not necessitate specific treatment. Similarly, this degree of pulmonary hypertension is often observed in patients with chronic obstructive pulmonary disease. Interestingly, in the latter population, a high prevalence of MetS was recently reported.189 Pulmonary hypertension may be associated with morbid obesity, particularly during exercise, and may be associated with hemodynamic evidence of pulmonary arteriolar hypertrophy.190,191 Obesity is also associated with sleep apnea and alveolar hypoventilation,192 alveolar hypoxia being the most potent stimulus for pulmonary vasoconstriction.
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Stroke |
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Numerous studies have reported an association between BMI and waist-to-hip ratio and stroke.193–201 Indeed, obesity is listed as a potential modifiable risk factor for stroke, but the independence of this relationship from cholesterol, hypertension, and diabetes was only recently identified.202 In the Physician’s Health Study prospective cohort of 21 414 men, overweight men (25 to 29.9 kg/m2) had a significant multiple-adjusted relative risk for total stroke of 1.32, for ischemic stroke of 1.35, and for hemorrhagic stroke of 1.25 as compared with men with BMI <25 kg/m2. Obese men (>30 kg/m2) had significant multiple-adjusted relative higher risks (1.91, 1.87, and 1.92, respectively) as compared with men with a BMI <25 kg/m2.202 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.202 The increase of stroke in obesity may be predicted by the prothrombotic/proinflammatory state that so often accompanies excessive adipose tissue accumulation.203,204
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Coronary Artery Disease |
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Pathogenesis
Atherosclerosis begins in childhood (5 to 10 years) as deposits of cholesterol esters in monocyte-derived macrophage foam cells in the intima of large muscular arteries (fatty streaks).205,206 Important early events in the development of atherosclerosis are endothelial cell dysfunction in the epicardial vessels, resistance vessels, or both, and inflammation of the vessel wall. In the setting of the insulin resistance of obesity, coronary endothelial dysfunction is seen at the level of the resistance vessels. However, in older individuals, the effect of adiposity and body fat distribution on endothelial dysfunction may be less important than in young subjects.207 Individuals at high risk for CHD can be identified through the measurement of carotid intimal-medial thickness (IMT), a marker of generalized atherosclerosis. Despite its limitations,208,209 carotid IMT among adults is associated with obesity and other CHD risk factors and cardiovascular events.210–213 Carotid IMT at age 35 years has been correlated with BMI measured throughout life, and childhood levels of BMI are associated with carotid IMT only among obese adults.214 This emphasizes the adverse, cumulative effects of childhood obesity that persist into adulthood.
As individuals age, the atherosclerotic lesion becomes more complex. Of importance, the distinction of the lipid-filled "vulnerable" plaque from the fibrous "stable" lesion becomes important for the development of acute coronary syndromes.215,216 In adults, obesity is often associated with advanced atherosclerosis. Indeed, postmortem examination of arteries from individuals 15 to 34 years of age (Determinants of Atherosclerosis in Youth [PDAY] 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.217–220 Obesity in young men, as crudely defined by the BMI, was associated with both fatty streaks and raised lesions in the RCA. Black subjects had more extensive fatty streaks than did white subjects in all arterial segments examined, and men did have more extensive raised lesions in the RCA than did women.221 Importantly, when BMI and abdominal panniculus thickness were simultaneously considered in men, a BMI 30 kg/m2 was associated with raised lesions in the RCA only among individuals with a large panniculus thickness (17 mm), which reinforces the concept that central fat distribution is more important than total fat as a risk factor for atherosclerosis.221 Moreover, this association between adiposity and RCA lesions remained significant after adjustment for other risk factors, eg, non-HDL and HDL cholesterol concentrations, hypertension, smoking, and glycohemoglobin.222 In fact, these covariates accounted for only 15% of lesion volume in these young obese subjects. This has been reinforced in a younger cohort of men in whom the maximal density of macrophages per square millimeter in the lesions was associated with visceral obesity.223 Of note, raised lesions in coronary arteries observed in young women lagged behind those seen in young men by 10 to 20 years.19,20,222,224 The preferential deposition of fat centrally after the menopause may explain in part why the risk for CHD events increases 10 to 20 years later in women than men.19,20,225 Overall, the data from the PDAY study provide convincing evidence that obesity in adolescents and young adults accelerates the progression of atherosclerosis decades before the appearance of clinical manifestations. Prospective studies that have reported follow-up data over >2 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.37,226–228 On the other hand, in patients with known CVD or after acute myocardial infarction, overall obesity as assessed by BMI is inversely related to mortality.229,230 Abdominal obesity appea