Obesity is turning into a global epidemic [1,2], and, in the last decade, the United States has seen a dramatic increase in obesity in both children and adults [3-5]. The body mass index (BMI) is used to classify overweight and obesity. BMI (weight in kg/height2 in meters) is frequently used as a surrogate measure of fatness in children and adults. A BMI of 25.0 to 29.9 kg/m2 in adults defines overweight, while a BMI ≥30.0 kg/m2 defines obesity. The classification issued in 1998 by a National Heart, Lung and Blood Institute task force is shown in Table 1, along with the disease risk associated with increasing BMI [6]. The epidemic of obesity that began in the 1980s has been tracked through the end of the century using BMI [4,7], and, in 1994, the National Center for Health Statistics [NCHS] reported from the first 3 years of the National Health and Nutrition Examination Surveys (NHANES) [8]. The NCHS noted that, between 1988 to 1994 (NHANES II) and 1999 to 2000 (NHANES III), the prevalence of overweight in adults increased from 55.9% to 64.5%, whereas the prevalence of obesity increased from 22.9% to 30.5% [4,5,9]. This increment in the prevalence of obesity was unanticipated [10,11]. More recently, the American Heart Association addressed and reviewed various approaches to the management and treatment of obesity involving weight loss [12]. In addition to an unfavorable risk factor profile, overweight and obesity also impact heart structure and function. Moreover, the clinical cardiovascular evaluation of obese patients may be compromised by the morphology of the patient.
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TABLE 1. Disease risk for type 2 diabetes, hypertension, and cardiovascular disease relative to waist circumference and BMI |
"AT RISK" OBESITY
The incidence of overweight and obesity has risen dramatically worldwide, resulting in a marked increase in the number of cases of metabolic syndrome (MetS), a clustering of cardiovascular risk factors including central adiposity, insulin resistance, hypertension, dyslipidemia, and a proinflammatory state. In order to describe the syndrome better, several definitions of MetS have been published, and the topic has recently been reviewed [13]. Table 2 gives the numerous definitions. However, uncertainty regarding its pathogenesis has cast some doubt upon MetS as a "syndrome" and as a risk marker for cardiovascular disease (CVD) [14]. Nonetheless, MetS may be associated with the global epidemic of obesity and diabetes [15]. With elevated risk not only of diabetes but also of CVD from MetS [16], an urgent need exists for the development of strategies to stop the emerging global epidemic of obesity [15].
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TABLE 2. Comparison of World Health Organization, European Group for the Study of Insulin Resistance and ATPIII definitions of the metabolic syndrome
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MetS can present in a variety of ways which are aligned to the components constituting the syndrome (Table 2) [17]. Of note, abdominal obesity is a risk factor for CVD worldwide and is probably better than BMI as a clinical surrogate marker for obesity [18,19]. This has been reported in men [20], in women [21], and in large cohorts [18,19,22-27]. Estimates of years of life lost due to obesity differ among races and between genders. It has been estimated that the optimal BMI for adults aged 18 to 85 years is 23 to 25 for whites and 23 to 30 for blacks [28]. MetS is associated with increased risk of diabetes [16] and CVD [22-25,29]. In the DECODE study involving European men and women, nondiabetic persons with MetS had an increased risk of death from all causes, including CVD [29]. Overall hazard ratios for all-cause and CVD mortality in persons with MetS compared to persons without it were 1.44 and 2.26 in men and 1.38 and 2.78 in women, respectively, after adjustment for age, blood cholesterol levels, and smoking. In two other European prospective studies [22,23], the presence of MetS also predicted increased CVD and coronary heart disease (CHD) mortality. Again, this is not unexpected, given that MetS includes established risk factors for CVD. On the other hand, measures of insulin resistance add incremental value to the clinical diagnosis of MetS in association with coronary artery calcification [30]. Finally, the improvement in the recognition and management of risk factors that has developed through the years in modern cardiology may be counteracted by the incidence of obesity, since it has been suggested that the life-shortening effect of obesity could increase as the obese who are now young carry their elevated risk of death into middle and old age [31].
The obesity epidemic 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 [32]. From the time (more than 10 years ago) of the early twin and adoption studies, large groups of individuals have been evaluated for genetic defects related to the development of obesity [33,34]. The genetic defects can be divided into two groups-the rare genes that produce significant obesity and a group of more common genes that underlies the propensity to develop obesity, the so-called susceptibility genes [32,35]. Indeed, 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 [36,37]. Research on the obesity genome has identified more than 41 sites as possible links to the development of obesity in a favorable environment [32].The identification of genes that are involved in monogenic, syndromic, and polygenic obesity has greatly increased our knowledge of the mechanisms underlying this condition [38]. It is important to assess the gene-environment obesity relation, since the prevalence of obesity, especially in children, is likely to continue rising. With obesity occurring at younger ages, the children and young adults of today will carry and express obesity-related risks for more of their lifetimes than previous generations.
CARDIOVASCULAR ADAPTATION OF OBESITY
Obesity is associated with numerous comorbidities, such as CVD, type 2 diabetes mellitus, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD [39,40], and CVD risks have been documented in obese children [7,41]. Indeed, there is a relationship between BMI in adolescence and all-cause mortality [3]. After a follow-up of 31.5 years, using subjects with a BMI between the 25th and 75th percentiles as controls, it was reported that a BMI above the 95th percentile in adolescence predicted adult mortality in both males (80% increment) and females (approximately 100% increment). A 30% increase in all-cause mortality was also seen in females and males when baseline BMI was between the 85th and 95th percentiles [3]. Cardiovascular mortality was not reported in that study. After 55 years of follow-up, another study reported an excess mortality among males, but not females, who were overweight in adolescence (BMI >75th percentile in the U.S. reference population) compared with those who were lean (BMI 25th-49th percentiles). The observed increased risk of death was independent of adult BMI [42]. In sum, obesity is associated with an increased risk of morbidity and mortality and is associated with reduced life expectancy [28,31,43-47].
In addition to an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual, even in the absence of comorbidities, as adipose tissue accumulates in excess amounts [48]. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, insulin resistance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, as well as via as yet unrecognized mechanisms.
ADAPTATION OF THE CARDIOVASCULAR SYSTEM IN OBESITY
Adipose tissue circulation
Over 100 years ago, it was understood that adipose tissue is surrounded by an extensive capillary network [49]. 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 [50,51]. Resting blood flow is
usually 2 to 3 mL/min/100 g of adipose tissue [52,53] and can increase about 10-fold. This increment is still lower (approximately 20 mL/min/100 g) compared to the increment seen in skeletal muscle (50-75 mL/min/100 g) [54]. Adipose tissue blood flow increases after meal intake [55], but this modulation is variable and may be decreased in patients with MetS [56,57].
Also, a substantial proportion of total body weight is made up of adipose tissue. Consequently, a large quantity of fluid is present in the interstitial space of adipose tissue, since the interstitial space is approximately 10% of the tissue-wet weight [58]. This could be important in the regulation of intravascular volume if this third space volume is mobilized into the circulation. The presence of excess fluid in this compartment may have important repercussions in obese individuals with heart failure if the extra volume is redistributed into the circulation. However, modulation of blood flow through adipose tissue typically prevents this from occurring in most stressful situations. Indeed, decrease in blood flow in response to hypovolemia (hemorrhagic shock) is more important in adipose tissue compared to other tissues, since the increase in epinephrine levels decreases blood flow more significantly in adipose tissue than in other sites (Table 3). This is because blood flow in adipose tissue is regulated by β1 receptors that mediate vasodilation, in contrast to the mainly β2 receptors in skeletal muscle [51]. There is extensive adrenergic innervation of vessels in adipose tissue, which finely regulates perfusion. 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, i.e., from 2.36 mL/min/100 g to 1.53 mL/min/100 g of adipose tissue (approximately 35%) in patients who have 15% to 26% body fat compared to those with >36% body fat [53]. Accordingly, the increase in systemic blood flow seen in obesity cannot be explained solely by increased requirements caused by adipose tissue perfusion, since the enlarged vascular bed of adipose tissue is less vascularized than other tissue. The concomitant increase in lean body mass in these individuals most likely accounts for some of the increased cardiac output [59]. Indeed, it has been reported that stroke volume, cardiac output, and left ventricular mass may be more related to fat-free mass than fat mass per se [59,60].
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TABLE 3. Tissue blood flow during experimental hypovolemia |
The adipose tissue is not simply a passive storehouse for fat but an endocrine organ capable of synthesizing and releasing into the bloodstream an important array of peptides and nonpeptide compounds which may play a role in cardiovascular homeostasis. Although this is not an extensive enumeration, adipose tissue is a significant source of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), resistin, lipoprotein lipase, acylation-stimulating protein (ASP), cholesteryl-ester transfer protein (CETP), retinal-binding protein (RBP), estrogens (through P-450 aromatase activity), leptin, angiotensinogen, adiponectin, insulin-like growth factor-I (IGF-I), insulin-binding protein 3 (IGFBP3), monocyte chemoattractant protein 1 (MCP-1), apelin, visfatin, zinc-α-2-glycoprotein and monobutyrin (Figure 1) [61-65]. Of clinical consideration, circulating concentrations of PAI-1, angiotensin II, C-reactive protein (CRP), fibrinogen, and TNF-α are all related to BMI [66-74]. It has been estimated that, in vivo, approximately 30% of the total circulating concentrations of IL-6 originate from adipose tissue [66,75]. This is of importance since 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 [76].
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Figure 1. Adipose tissue function as an endocrine and storage organ (TG). Adipose tissue also secretes numerous molecules implicated in steroid and lipid metabolism, the fibrinolytic system, and blood pressure regulation. On the other hand, the predominant source of free fat acids (FFA) for adipose tissue TG is LPL. Glucose incorporation into TG is mostly into the glycerol backbone. ASP facilitates both glucose uptake and TG synthesis (DGAT), whereas insulin increases glucose uptake and adipose tissue LPL. Adipose tissue TG provides FFA to other tissues by HSL-mediated lipolysis. This process is stimulated by cAMP and inhibited by insulin. |
Hemodynamic repercussions of obesity
Obesity produces an increment in total blood volume and cardiac output due, in part, to the increased metabolic demand induced by excess body weight [77,78]. Thus, at any given level of activity, the cardiac workload is greater for obese subjects. It has been demonstrated that for most obese people walking implies an exercise of moderate to high intensity [79,80]. Obese subjects have higher cardiac output and lower total peripheral resistance (if the patient is not hypertensive) than lean individuals. The increased cardiac output is attributable mostly to increased stroke volume, since heart rate increases little if at all [81,82]. For any given level of arterial pressure, cardiac output is higher and peripheral vascular resistance lower in an obese individual compared to a nonobese individual. Both stroke volume and cardiac output are higher in men than women (approximately 10%) and in overweight than normal weight individuals (approximately 9%) [59]. Of interest, these differences are eliminated after adjusting for free fat mass or body surface area [59]. Also, the Frank-Starling curve is shifted to the left in obesity due to incremental increases in left ventricular filling pressure and volume, which over time may produce chamber dilatation. Ventricular chamber dilatation may then lead to increased wall stress, which, in an attempt to normalize wall stress, predisposes to an increase in myocardial mass and ultimately to eccentric left ventricular hypertrophy (LVH) [83,84]. 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 but may simply reflect a physiological adaptation to the expanded blood volume [85]. As a consequence, left atrial dilatation may mediate the excess risk of atrial fibrillation associated with obesity [86]. However, LVH in long-standing obesity and/or the effects of concomitant hypertension may also be contributing factors to left atrial enlargement. Left ventricular end-diastolic cavity dimension, increased left ventricular mass, and left atrial diameter may be early markers in the sequence of cardiac abnormalities occurring with increasing BMI [87].
Weight loss through diet and exercise is recommended in the management of obesity [12]. It is important, however, to recognize that the obese individual may be limited in terms of exercise capacity, since obesity is associated with persistence of elevated cardiac filling pressures during exercise [88,89]. Cardiac output is able to increase sufficiently to accommodate mild to moderate exercise workloads. Increased cardiac output during exercise is typically accompanied by an increase in left ventricular filling pressure, often exceeding 20 mmHg. 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 [81]. This is consistent with a high-pressure system and, accordingly, obese patients may show higher right heart filling pressures, systolic pressure, cardiac output, and pulmonary vascular resistance index [78]. 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 loss, and relief of edema and dyspnea, when present, may accompany this improvement [81].
Effects on ventricular function
Eccentric LVH, which is commonly present in morbidly obese patients (BMI ≥40 kg/m2), is often associated with left ventricular diastolic dysfunction. Moreover (as is the case with left ventricular mass), obesity of longer duration is associated with poorer left ventricular systolic function and greater impairment of left ventricular diastolic function [90]. Because of the presence of non-specific symptoms, evaluation for left ventricular diastolic dysfunction is important clinically in obese subjects [40,91-93]. Age and cardiac hypertrophy of the concentric [94,95] or, more commonly, the eccentric type [96,97] predispose over time to left ventricular systolic dysfunction. Although postmortem studies have demonstrated a relationship between heart weight and body weight [94,98], obese patients without concomitant comorbidities may initially be afflicted only by diastolic dysfunction and hyperkinetic systole without LVH when indexed by fat-free mass [97]. In humans and most animal models, the development of obesity leads not only to increased fat deposits 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 two possible ways. First, 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 a variety of locally acting molecules. Second, lipid accumulation can occur in nonadipose cells and may lead to cell dysfunction or cell death, a phenomenon known as lipotoxicity [99-101]. Abnormal cellular adaptations may impact the cardiac muscle unfavorably in several ways leading to cardiomyopathy.
Cardiomyopathy of obesity (adipositas cordis)
Adipose tissue is a normal component of the myocardium, but it is fundamentally important to differentiate between normal and pathological conditions of it. In the normal heart, the adipose tissue, in proportion to body weight, age, and sex, is usually distributed underneath the epicardium around the atrioventricular and interventricular sulci, but it can also be found in the thickness of the wall, especially on the right ventricle, and even underneath the endocardium [102,103]. Obesity cardiomyopathy is considered present when cardiac structural (left ventricular dilatation) and hemodynamic (increased left ventricular wall stress) adaptations result in congestive heart failure. Right ventricular structure and function may be similarly affected. This entity, obesity cardiomyopathy, was recognized as early as 1818 [104]. The case described by Cheyne 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 [104]. Subsequently, other reports were published of excessive epicardial fat and fatty infiltration of the myocardium in the hearts of obese subjects that related the anatomical change to cardiac dysfunction [98,105].
Myocardial fat infiltration is more prevalent in women than men and, with an incidence of approximately 3%, is an uncommon autopsy finding [106,107]. In general, the right ventricle is more likely to be involved than the left ventricle and the anterior wall is involved to a greater extent than the posterior. In individuals in whom uncomplicated fatty infiltration occurs, the pathology consists of areas of fat surrounded by fibrosis unattached to epicardial fat [77]. In most cases, cardiac hypertrophy is a direct reflection of BMI, and the hypertrophy is due to myocyte change rather than excessive fat infiltration or fibrosis [108]. Although the limitations of endomyocardial biopsy are well known [109], structural myocardial biopsy findings seeking a specific cause of congestive heart failure may be disappointing in obesity and provide fewer diagnoses based on histology than in lean patients [78]. Indeed, idiopathic dilated cardiomyopathy was found in 77% of obese subjects in this series but in only 36% of lean subjects. Not surprisingly, the most common finding on endomyocardial biopsy in the obese group was mild myocyte hypertrophy [78]. It is important to differentiate fatty infiltration of the heart from right ventricular dysplasia, which is an arrhythmogenic cardiomyopathy characterized by fibrous and/or adipose tissue replacement in the myocardium. Nevertheless, there is a quantitative difference on right ventricle biopsy with respect to fibro-adipose tissue in normal hearts and in cases with right ventricle dysplasia [102,110].
It is important to remember that, in obesity, excess adipose tissue on the surface of the right ventricle represents an exaggeration of normal architecture. Initially, the fatty heart is probably not an infiltrative process but most likely a metaplastic phenomenon [106].
Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another [111]. It may represent an adaptative substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment. Cells can gradually accumulate fat between muscle fibers and/or cause myocyte degeneration, resulting in cardiac conduction defects [112,113]. These cords of fat cells may also emanate from epicardial fat [106]. When the right ventricle is involved, the sinus node musculature, the atrioventricular node, the right bundle branch [112], and, ultimately, the entire myocardium of the atrioventricular region can be replaced by fat [113]. A pattern of restrictive cardiomyopathy occasionally develops [114,115]. In this situation, small irregular aggregates and bands of adipose tissue separate myocardial cells, possibly a result of pressure-induced atrophy from the intervening fat [114]. As discussed above, an alternative explanation could be the lipotoxicity of the myocardium induced by free fatty acids, which can cause apoptosis of lipid-laden cells such as cardiomyocytes [116]. Typically, in the cardiomyopathy of obesity, the thickness of the atrial septum is increased (lipomatous hypertrophy), but myocardial fatty infiltration has also been described without any relationship to obesity [115]. Finally, adipose tissue may also be deposited on cardiac valves and may produce valvular dysfunction [117].
Cardiac evaluation in animal models of obesity
It is possible to evaluate cardiac dimensions and ventricular function in small animals such as pigs, dogs, rabbits, rats, and mice [44,118-123]. Transthoracic echocardiography is a noninvasive technique that adequately provides information about cardiac structures and function, while, on the other hand, transesophageal echocardiography allows a qualitative estimation of the rat heart [118]. Intracavitary ultrasound can be used to assess the endocardium, ventricular function, and dimensions of the heart in open-chest studies in rats [118]. Classic animal models of obesity and insulin resistance have been the ob/ob mouse and the obese Zucker rat. In the ob/ob mouse model, the obesity gene product is leptin, and leptin deficiency explains the obesity in these mice [124]. Leptin receptors are present in the heart [125-127], and leptin has been shown to have an impact on cardiovascular structural remodeling [128]. Indeed, leptin deficiency in ob/ob mice has been shown to lead to ventricular hypertrophy independently of body mass [128]. Moreover, exogenous leptin administration reduced ventricular hypertrophy.
Other mouse models of obesity are the New Zealand obese mouse and the agouti mouse. In the obese Zucker diabetic fatty (ZDF) rat [fa/fa], a model of obesity secondary to genetic unresponsiveness to leptin, it has been reported that cardiac dysfunction in obesity is caused by lipoapoptosis, while myocardial triglycerides are high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-α [116].
Indeed, nonadipocytes have very limited capacity to store excess fat, and if these cells are exposed to high levels of plasma lipids, as usually occurs in obesity, they may undergo steatosis and loss of systolic function [116]. Similarly, in the ob/ob mouse model, cardiac lipid accumulation is paralleled by diastolic dysfunction [129].
Adiponectin, which is a circulating adipocyte-derived cytokine, may also play a role in cardiac remodeling, where it inhibits hypertrophic signalling in the myocardium through activation of AMPK signalling [130]. These animal models may help to better characterize obesity-related cardiac abnormalities in humans.
FREQUENTLY PERFORMED PROCEDURES IN CARDIOLOGY: ASSESSMENT OF OBESE INDIVIDUALS
History and physical examination
The presence and extent of cardiac dysfunction in obese patients is often underestimated by the physical examination and electrocardiogram. Dyspnea on exertion and lower extremity edema are often nonspecific signs of heart disease in obesity [80,91,131], and it may be difficult to assess an obese individual clinically due to several limitations inherent in the subject's morphology. A continuum probably exists in terms of cardiovascular manifestations from the overweight to the morbidly obese, since symptoms and signs of obesity cardiomyopathy occur mainly in patients with a relative weight ≥175% or a BMI ≥40 kg/m2 [77]. 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 be used to 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 [132]. One must take into consideration, however, that these veins are sometimes relatively full in spite of little or no increase in pressure and, conversely, that venoconstriction may collapse the veins despite an elevated central venous pressure. In the very obese patient, symptoms of heart disease may remain nonspecific, but the clinician should search carefully 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 inter-space [133]. This is significant because pulmonary artery systolic pressure (PASP) has been reported to be above the suggested normal limit (≤30 mmHg) in 51% of obese patients [134], and, for each increase in BMI, the PASP is increased by approximately 0.1 to 0.4 mmHg [134]. Poor peripheral venous access in obese patients may necessitate more frequent use of central venous lines. A short stubby neck, loss of physical landmarks, and a greater skin-blood vessel distance make internal jugular and subclavian vein cannulation in the coronary care unit technically more difficult [135].
Radiology
In obesity, the chest X-ray generally shows an elevated diaphragm and the heart widened in a horizontal direction with its apex displaced outward to the left [136].
The heart appears enlarged and the left ventricle hypertrophied, based on the criterion of a total transverse heart diameter more than half the maximum internal thoracic diameter. This frequently is at odds with the findings on the surface electrocardiogram (see below).
The apex or the lower portion of the left border of the heart could be hazy in outline, owing to the presence of apical pericardial fat [136]. Moreover, portable bedside radiographs are usually very low quality in obese patients, limiting the value of this important diagnostic tool in emergencies. Also, many CT scan tables have weight restrictions (about 160 kg) that can prohibit imaging of severely obese patients.
The electrocardiogram
Like the physical evaluation, the electrocardiogram (ECG) is influenced by morphological changes caused by obesity, such as:
1. in the supine position, 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 caused by the accumulation of adipose tissue in the subcutaneous tissue of the chest wall (and possibly increased epicardial fat) [137],
4. any associated chronic lung disease secondary to sleep apnea/hypoventilation syndrome.
Several changes in the ECG occur as obesity increases (Table 4). Besides low QRS voltage and leftward trend in the axis, other alterations frequently 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 [136,138,139]. More frequent ST segment depression is seen in overweight patients with CHD [140], and insulin concentrations may be related to the development of ST-T segment abnormalities over time [141]. Weight loss induces a rightward shift of the QRS axis [142,143], but conduction intervals (duration of the P wave, QRS complex, and the PQ interval) are not affected by weight loss [143] since they are often not clinically different from those of lean subjects [138].
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TABLE 4. ECG changes that may occur in obese individuals |
An increased incidence of false-positive criteria for inferior myocardial infarction has been reported both in obese individuals and in women in the final trimester of pregnancy. This is presumably due to elevation of the diaphragm [144].
LVH is strongly associated with cardiac morbidity and mortality [145]. Multiple ECG criteria for LVH are present more regularly in the morbidly obese compared to lean individuals but less frequently than would be expected based on the high prevalence of echocardiographic criteria for LVH in these patients [138]. Therefore, LVH is probably underdiagnosed by the usual ECG criteria in morbidly obese individuals.
A low frequency of LVH defined by voltage criteria is seen in morbid obesity where LVH was demonstrated in two-thirds of the obese subjects by echocardiography [138,146,147].
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 (Figure 2).
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Figure 2. |
In 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 because diaphragmatic expansion is restricted due to the abdominal pannus. Thus, it has been proposed that for men of all ages, LVH is considered present based on 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 of all ages, the same criteria were set at >25 mm [148]. 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 (Table 5).
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TABLE 5. Detection of left ventricular hypertrophy by QRS voltage in obesity |
These percentages (representing the Cornell score) 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 seem to be less influenced by the presence of obesity [149]. Although ECG parameters in obese patients should be expected to change after weight loss, the impact of weight loss in obese patients on QRS voltage is not consistent. Studies report a decrease [150-152], no change [153], and an increase in the QRS amplitude [139,142,143].
Following weight loss, a decreased amount of fat mass may counterbalance a true decrease in left ventricular mass, and low QRS voltage could be secondary to myocardial atrophy [152,154,155].
Thus, these opposite vectors may negate the resulting QRS amplitudes. One study [142] demonstrated that substantial weight loss in morbidly obese patients resulted in a decrease in voltage in ECG criteria that are less reliant on precordial voltage (R wave in lead aVL), whereas the frequency with which LVH was diagnosed increased using precordial voltage (SV1 + RV5 or RV6).
Accordingly, regression of LVH following weight loss should be evaluated using ECG criteria less influenced by anterior chest wall fat.
Echocardiography
In the past, the cardiac status of obese individuals was difficult to assess, and obesity-induced cardiac abnormalities were found only postmortem [94,98,104,106, 107,136,156-159]. Even since the development of echocardiography, transthoracic echocardiography can be difficult from a technical standpoint to perform in obese patients [160,161]. Subepicardial adipose tissue is often difficult to distinguish from pericardial effusion in obese patients [161,162]. Epicardial adipose tissue is known to be a common source of false-positives for effusion (pseudopericardial effusion), and an adipose tissue deposit may cause underestimation of the amount of pericardial fluid [157,163]. Interestingly, free wall right ventricle epicardial adipose tissue detected by echocardiography is strongly correlated to waist circumference and visceral adipose tissue [164]. Therefore, epicardial adipose tissue may release short-lived deleterious cytokines locally as if it presented characteristics of a true visceral fat tissue [165]. Adipose tissue can also be found within the heart, i.e., in the interatrial septum. From descriptions at necropsy, the definition of lipomatous hypertrophy of the interatrial septum corresponds to a maximal transverse dimension of interatrial fat >20 mm [166,167]. In that circumstance, the adipose tissue may constitute a mean of 36% (range 27%-52%) of the total cardiac weight at necropsy [137]. It was also proposed that a marked increase in subepicardial fat may interfere with normal ventricular relaxation and ventricular diastolic filling [168]. Thus, lipomatous hypertrophy of the interatrial septum, a finding associated with obesity and advancing age, consists of accumulation of adipose - including fetal adipose - tissue, in the interatrial septum, cephalad and caudal to the fossa ovalis but always sparing the fossa, thus deliminating a "dumbbell" shape on 2-dimensional echocardiogram [169,170]. This accumulation of fat projects toward the right atrium.
Although, there are numerous indices of left ventricular diastolic filling derived from echocardiography and cardiac Doppler evaluation, the increased intravascular volume in obesity may mask the abnormalities of diastolic filling that Doppler otherwise would reveal. Pulmonary venous Doppler evaluation may be used, but if it is not technically feasible, transmitral Doppler imaging may properly evaluate the presence of left ventricular diastolic dysfunction [171,172]. Tissue Doppler has also been used to document diastolic dysfunction in obesity [173]. In order to evaluate left ventricular mass in obese subjects, indexing left ventricular mass using height2.13 or height2.7 has been proposed as more appropriate than normalization for body surface area or even height [174,175]. Another potential way to normalize left ventricular mass is with lean body mass [176,177]. Interestingly, following indexing using lean body mass, no gender differences on left ventricular mass were evident, and also the relative effects of adiposity and blood pressure on left ventricular mass were shown to be of similar magnitude [177]. This finding was underlined by the results of the Strong Heart Study cohort, which show that stroke volume and cardiac output are more strongly related to fat free mass than other variables, in both normal weight and overweight individuals [59]. Thus, obesity is associated with imaging limitations, i.e., echocardiography, chest x-ray, and changes in the ECG, that may affect the diagnosis of LVH and even CAD.
Undoubtedly, adiposity status impacts heart size and function, but the optimal indexing criteria to define LVH after an echocardiographic study in obese individuals remains to be refined and confirmed. Animal models of obesity will help to provide insight into the pathophysiological processes involved in the abnormalities of heart structure and function associated with obesity.
OBESITY AND ASSOCIATED COMORBIDITIES
Hypertension
The majority of patients with high blood pressure are overweight [178]. Hypertension is about six times more frequent in obese subjects than in lean men and women [178]. MetS is an often overlooked but relatively common condition in patients with primary hypertension. Its frequency has been reported to be around 30%, depending on the clinical characteristics and criteria used to define it [179,180]. Not only is hypertension more frequent in obese subjects than in normal weight controls, but weight gain in young people also is a potent risk factor for later development of hypertension. Each 10 kg in body weight over normal weight is associated with a 3.0 mmHg higher systolic and 2.3 mmHg higher diastolic blood pressure. These increases translate into an estimated increased risk for CHD of 12% and a 24% increase in risk for stroke [6]. However, results from NHANES III include more specific estimates for the prevalence of high blood pressure per age and BMI group [181]. Among men, the prevalence of high blood pressure increased progressively with increasing BMI, from 15% at a BMI <25>2 to 42% at a BMI of ≥30 kg/m2. Women showed a similar pattern to that of men, the prevalence of hypertension being 15% at a BMI <25>2 and 38% at a BMI of ≥30 kg/m2 [181]. The pattern of increased prevalence of high blood pressure with increasing BMI was similar for whites, blacks, and Mexican Americans of both genders, and the age-adjusted rates were highest among blacks at every BMI level [181]. It is well recognized that technical difficulties exist for the indirect measurement of blood pressure in the obese patient that may result in an overestimation of blood pressure [182-184].
Nevertheless, there is a strong association between obesity and higher than optimal blood pressure [185,186], and the increase in blood pressure is greatest when the obesity is distributed abdominally [183,187-190]. Factors to be considered in linking obesity to an increase in blood pressure are related to changes in cardiac output and peripheral vascular resistance. In the vast majority of hypertensive patients, the occurrence of major events results from long-term exposure to multiple risk factors and is usually preceded by the development of asymptomatic structural and functional abnormalities at the vascular and cardiac levels [191]. Obesity per se is associated with alterations in hemodynamics [192]. An increase in oxygen demand produced by excess adipose tissue (approximately 1.5 mL/kg/min) requires an increase in cardiac output. A parallel increase in blood volume occurs as well. Thus, obese individuals have increased blood volume, stroke volume, and cardiac output. This high-output state is associated with a reduction in peripheral vascular resistance in individuals with normal blood pressure. However, as alluded to above, obese persons with blood pressure at a greater than optimal level, i.e., hypertensives, have peripheral vascular resistance that is either inappropriately "normal" or increased.
Therefore, while 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. MetS links hypertension with an increase in visceral fat [189,193-195]. Insulin resistance has been proposed as a common mechanism linking the other components of MetS. Yet there are also differences among races in the relation between blood pressure and insulin resistance [196-198]. The sympathetic nervous system is one possible link between insulin resistance and increased blood pressure [199]. Overactivity of the sympathetic nervous system related to obesity is supported by data from the Normotensive Aging Study showing that urinary norepinephrine levels increase with BMI, abdominal girth, and insulin glucose levels [199]. The role of insulin, however, is cast in doubt by the observation that patients with insulinomas are not hypertensive [200], and chronic intrarenal hyperinsulinemia does not cause hypertension [201]. It has recently been 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 [189]. MetS is associated with subclinical organ damage (higher urinary albumin excretion and higher left ventricular mass) in nondiabetic, essential hypertensive patients [202]. Years ago, in MetS, the prevalence of hypertension (blood pressure >130/85 mmHg) was reported to be 80.1% for men and 40.7% for women [199]. More recently, racial differences by gender in terms of MetS-associated high blood pressure have been reported. Indeed, high blood pressure may vary from 3.9% in women and 17.1% in men 20 to 34 years of age to 70.3% in women and 80.7% in men ≥65 years of age [198]. Obviously, if lower blood pressure levels were considered optimal, hypertension would be almost universal in men [203].
The association of obesity with a "systemic inflammatory state" may provide one other mechanism for increased blood pressure. A strong correlation exists between obesity and IL-6 and CRP levels [204]. IL-6 is a pro-inflammatory cytokine that, among many other things, stimulates the production of CRP by the liver. Thus, obesity is somewhat similar to a low-grade systemic inflammation. Low-grade inflammation may play a role in increasing blood pressure [205]. Increases in systolic and diastolic blood pressures, pulse pressure, and mean arterial pressure were significantly associated with levels of IL-6, whereas increases in systolic blood pressure, pulse pressure, and mean arterial pressure were associated with levels of soluble ICAM-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 [205]. Regardless of the mechanisms involved, weight loss in obese individuals is associated with a decrease in blood pressure. In 50% or more of the population, the average decrease in diastolic blood pressure is 1 to 4 mmHg systolic and 1 to 2 mmHg diastolic per kilogram of weight lost as normalization of blood pressure [206-208]. Of note, after weight loss has ceased, the effect of weight loss on blood pressure may not always persist [209,210].
Significantly, the physician who evaluates a referred patient for hypertension should be very suspicious of obese patients who admit habitual snoring, nocturnal gasping or choking, witnessed episodes of apnea, and daytime sleepiness, and the physician should consider the diagnosis of sleep-disordered breathing [211-213].
Sleep Apnea
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. The result often is a ventilation-perfusion mismatch, especially in the supine position. Obstructive sleep apnea corresponds to repeated episodes of complete or partial upper airway closure during sleep [214]. Obesity is a classic cause of alveolar hypoventilation, and the prevalence of sleep-disordered breathing and sleep disturbances rises dramatically in the obese [215]. Obesity is by far the most important modifiable risk factor for sleep-disordered breathing [212,213]. Sleep apnea is an independent risk factor for hypertension, ischemic heart disease, and heart failure. An estimated 40 million Americans are afflicted with sleep disorders, and the vast majority of these patients remain undiagnosed [212,213]. Despite careful screening by history and physical examination, sleep apnea is revealed only by polysomnography in a significant number of patients [216]. Although some clinical pre-senting features exist that could be useful as screening tools to diagnose sleep apnea, a high index of suspicion is needed by clinicians, since diagnostic accuracy may be low [217]. The association of sleep-disordered breathing and sleep apnea with hypertension was studied in 6132 subjects over 40 years of age [218]. Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing severity of sleep-disordered breathing. That obesity might be a confounding factor has been considered, 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 linked processes, i.e., sleep apnea, hypertension, and atherosclerosis [219]. Although there is a link between sleep apnea and systemic hypertension, the association of obesity with both disorders confounds the relation. Since sleep apnea is associated with altered heart rate variability [220], the association between sleep-disordered breathing, hypertension, and abdominal obesity may be explained in part by altered heart rate variability. Given the specific role of recurrent nocturnal desaturation events in the determination of cardiovascular and metabolic risk factors [221,222], nocturnal oximetry can be considered a reliable tool in investigating the cardiovascular and metabolic risks associated with sleep apnea. However, it is important to remember that the clinical and electrocardiographic signs of cor pulmonale appear later than those of pulmonary hypertension assessed by right heart catheterization. From a cardiological standpoint, patients with sleep apnea have an increased risk of diurnal hypertension, nocturnal dysrhythmias, pulmonary hypertension, right and left ventricular failure, myocardial infarction, stroke, and mortality [223]. A number of treatments are available for sleep apnea, but weight loss in obese patients should always be advocated [214].
Stroke
Numerous studies have reported an association between BMI and waist-to-hip ratio and stroke [224-232]. Indeed, obesity is listed as a potential modifiable risk factor for stroke, but the independence of this relationship from cholesterol, hypertension, and diabetes has only recently been identified [233]. In the Physician's Health Study prospective cohort of 21,414 men, overweight men (BMI 25 - 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 compared with men with BMI <25>2. Obese men (>30 kg/m2) had significant multiple adjusted relative higher risks (1.91, 1.87, and 1.92, respectively) compared to men with a BMI <25>2 [233].
Each 1-unit increase in BMI was associated with an increase of 4% in the multiple adjusted risk for ischemic stroke and 6% for hemorrhagic stroke. However, stroke severity for ischemic stroke was not associated with BMI [233]. The increased risk for stroke in obesity may be predicted by the prothrombotic/proinflammatory state that so often accompanies excessive accumulation of adipose tissue [234,235]. Indeed, it has been demonstrated that MetS is associated with increased carotid atherosclerosis and fibrinolytic dysfunction, which both may predispose to stroke [236].
Coronary Artery Disease
Pathogenesis
Obesity is associated with abnormal endothelial function [237]. 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 stress [238] or be a result of proinflammatory cytokines. In the Framingham Heart Study, BMI was highly associated with systemic oxidative stress, as determined by creatinine-indexed urinary 8-epi-PGF2α levels [239]. A decrease in the function of NO would result in vasoconstriction and an increase in vascular resistance, which may predispose to CVD risk factors. Progressively worsening functional coronary circulation abnormalities of nitric oxide-mediated, endotheliumdependent vasomotion assessed with positron emission tomography occur as insulin resistance and carbohydrate intolerance increase in severity [240]. High levels of resistin, a plasma protein produced mainly by macrophages in humans, are found in the obese and insulin-resistant patients [241,242]. Resistin may provide insight into any links between obesity, inflammation, and atherosclerosis in humans, since plasma resistin levels are correlated with markers of inflammation and increasing coronary artery calcification [30]. Atherosclerosis begins (between 5 and 10 years of age) as deposits of cholesterol esters in monocytederived macrophage foam cells (fatty streaks) in the intima of large muscular arteries [243,244]. 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. Coronary endothelial dysfunction is seen at the resistance vessel level in the insulin resistance setting of obesity. However, in older individuals the effect of adiposity and body fat distribution on endothelial dysfunction may be less important than in the young [245]. Individuals at high risk for CHD can be identified by measurement of carotid intimal-medial thickness (IMT), a marker of generalized atherosclerosis. Despite limitations [246,247], carotid IMT among adults is associated with obesity and other CHD risk factors and cardiovascular events [248-251].
Carotid IMT at age 35 years has been correlated with BMI measured throughout life, and childhood BMI is associated with carotid IMT only among obese adults [252].This relationship emphasizes the adverse, cumulative effects of childhood obesity that persist into adulthood. As individuals age, the atherosclerotic lesion becomes more complex. Notably, the distinction between the lipid-filled "vulnerable" plaque and the fibrous "stable" lesion becomes important for the development of acute coronary syndromes [253,254]. In adults, obesity is often associated with advanced atherosclerosis. Indeed, examination of arteries post-mortem from individuals 15 to 34 years of age (Pathobiological Determinants of Atherosclerosis in Youth [PDAY] study) who died in accidents, from homicide, or from suicide 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 is associated with obesity and with the size of the abdominal panniculus [255-258]. Obesity in young men, as crudely defined by BMI, was associated with both fatty streaks and raised lesions in the RCA. Black subjects had more extensive fatty streaks than white subjects in all arterial segments examined, and men had more extensive raised lesions in the RCA than women [259]. 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), reinforcing the idea that distribution of fat centrally is more important than total fat as a risk factor for atherosclerosis [259]. Moreover, the association between adiposity and RCA lesions remained significant after adjusting for other risk factors, i.e., non-HDL and HDL cholesterol concentrations, hypertension, smoking, and glycohemoglobin [260]. In fact, these covariates accounted for only 15% of lesion volume in these obese young subjects. The association has been reinforced by a study of a younger cohort of men where the maximal density of macrophages/mm2 in the lesions was associated with visceral obesity [261]. Macrophage-rich plaques in adolescents with large amounts of visceral fat may have the potential to progress rapidly. This is important because unstable plaques rich in macrophages and lipids are considered the most dangerous relative to the occurrence of acute coronary syndrome. Moreover, reduced coronary flow reserve is significantly related to body fat distribution and insulin resistance [262]. Adiponectin, a collagen-like protein, is synthesized by the adipocytes. It correlates negatively with age, BMI, insulin resistance, and CRP [263,264]. Adiponectin accumulates in damaged vascular walls and modulates beneficially the endothelial inflammatory response to vascular injury [265,266]. Similar to resistin, adiponectin has been proposed as a link in the adipose-vascular axis [267] and may play a role in the development of atherosclerosis. Indeed, low plasma adiponectin levels have been associated with progression of coronary artery calcification independently of other cardiovascular risk factors [268].
Of note, raised lesions in coronary arteries observed in young women lagged behind in timing of presentation by 10 to 20 years those seen in young men [18,19,260,269]. 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 [18,19,270]. The relationship between MetS, presence of angiographically significant CAD, and incident CVD events was evaluated prospectively in the Women's Ischemia Syndrome Evaluation (WISE) study [271]. Twenty-five percent of the cohort presented MetS at entry. Compared with women with normal metabolic status, women with MetS or diabetes had a significantly lower 4-year survival rate (3.5% absolute) and event-free survival from major adverse CVD events (death, nonfatal myocardial infarction, stroke, congestive heart failure; 5.7% absolute). Thus, MetS modulates the CVD risk associated with angiographic CAD in women suspected of myocardial ischemia [271].
Overall, the data provide convincing evidence that obesity in adolescents and young adults accelerates atherosclerosis decades before clinical manifestations are evident. Prospective studies that have reported follow-up data over more than two decades, such as the Framingham Heart Study, the Manitoba Study, and the Harvard School of Public Health Nurses Study, show that obesity is an independent predictor of clinical CHD [43,272-274]. On the other hand, in patients with known CVD or post-AMI, overall obesity as assessed by BMI is inversely related to mortality [275,276]. 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) registry, the mortality rate for abdominally obese patients was increased 23% compared to patients who were not. Exclusion of diabetes and hypertension from the multi-variate analysis did not alter the findings. This implies that the impact of obesity on all-cause mortality is mediated via other mechanisms than traditional risk factors such as hypertension and diabetes [276]. Of note, patients with marked increase in subepicardial fat have an increased frequency of cardiac rupture following AMI [277].
Assessment of coronary artery disease with imaging techniques
The assessment of CHD with imaging techniques is important in obese patients. As discussed earlier, since baseline ECG may be influenced by obesity (false positive for inferior myocardial infarction, microvoltage, nonspecific ST-T changes) and obese patients may have impaired maximal exercise testing capacity (dyspnea, orthopedic limitations, left ventricular diastolic dysfunction), other modalities may be of interest in the evaluation of CHD in this population. Although attenuation correction has been developed for single photon emission computed tomography (SPECT), attenuation artefacts, most commonly resulting from attenuation by the diaphragm or breast, are common in obesity. However, significant clinical CHD may be adequately evaluated in obese subjects with nuclear cardiology imaging [278-280]. Due to impaired exercise tolerance because of mechanical and physiological limitations related to stress testing in very obese patients [80], a dipyridamole thallium201 or technetium99m perfusion scan may be used instead of exercise testing for evaluating the presence of ischemic heart disease. The specificity of SPECT may be slightly greater with technetium99m than thallium201, in part because of its higher energy (140 vs 70 keV), but both isotopes pose an interpretation problem if accurate attenuation correction and gating is not performed. Although differences in tracer distribution may be seen, prolonged transmission scanning (5 seconds vs 10 seconds per view) with thallium201 is not mandatory for accurate clinical interpretation in obese compared to lean patients after correcting for the attenuation factor due to obesity [281]. Triple head simultaneous emission transmission tomography using technetium99m is also accurate in obesity [282]. It is important to note that attenuation artefacts with thallium201 may limit identification of subgroups of patients since concordance of SPECT with positron emission tomography (PET) is lower for the RCA territory [280]. Nevertheless, in severe obesity, a higher incidence of false-positive noninvasive functional tests for the detection of CHD is seen [282,283]. Coronary calcification is associated with cardiac events and the likelihood of inducible myocardial ischemia [284-286]. MetS is also associated with an increased likelihood of inducible myocardial ischemia using myocardial perfusion scintigraphy [287]. These findings are of interest with respect to the controversy surrounding the cardiac risk associated with MetS [14,288].
Transesophageal echocardiography (TEE) may be of diagnostic use in the evaluation of the presence of ischemic heart disease in the severely obese. Even if these patients tend to have a higher prevalence of sleep apnea, episodes of oxygen desaturation are not increased during TEE in patients with moderate obesity but were shown to be more common (6.7%) in morbidly obese patients [289]. Transesophageal dobutamine stress echocardiography combines the advantages of pharmacologic stress testing with superior-quality cardiac imaging and has been reported safe and a good alternative to cardiac catheterization for assessing the presence of CHD and ischemic threshold in morbidly obese patients [290]. Evaluation of obese patients may be limited due to the fact that the examination table for nuclear medicine and catheterization usually does not accommodate the very obese. If cardiac catheterization is contemplated, femoral access may not be ideal, not only because of the volume of adipose tissue present but also because of the presence of intertrigo. Concerns about severely obese patients include the adequacy of standard angiographic equipment for imaging and potential procedural complications, particularly related to femoral access and hemostasis. Nevertheless, the use of femoral closure devices may help to decrease bleeding complications. Alternatively, the percutaneous radial approach has numerous advantages in the very obese patient since the frequency of complications using it is very low [283,291].
Coronary artery disease revascularization procedure in obesity
Among the 9405 patients evaluated from 1986 to 1997 at the Duke University cardiac catheterization laboratory, the prevalence of obesity has increased from 20% to 33% [292]. Characteristics of obese patients in the catheterization lab are younger age and more comorbidities, but with more single-vessel disease at baseline [292,293]. Obesity was also associated with more clinical events over the post-30-day period after cardiac catheterization, with higher cumulative inpatient medical costs as well as significant differences in unadjusted survival at 10 years [292]. Prospective evidence, after only a 4-year follow-up, shows that abdominal obesity in men is associated with accelerated progression of carotid atherosclerosis independent of overall obesity and other risk factors [294]. The association between abdominal obesity and carotid atherosclerosis was found to be particularly evident when accompanied by a serum apolipoprotein B ≥1.01 g/L and increased prevalence of small dense LDL [294]. Also, abnormal glucose tolerance may be an important determinant of long-term prognosis after coronary angioplasty [295], which may be dependent on the features of MetS [296]. Following coronary artery bypass surgery, the components of the insulin resistance syndrome are associated with angiographic progression of atherosclerosis in nongrafted coronary arteries [297]. Therefore, abnormalities of glucose metabolism with features of MetS could modulate the extent of atherosclerosis within the coronary artery tree and modulate acute coronary syndrome events [298,299].
Cardiac surgeons often perceive obesity as a risk factor for adverse perioperative outcomes following coronary artery bypass surgery (CABG). The Parsonnet risk stratification scoring system attributes a score of 1 point to patients with morbid obesity, which is defined as >1.5 times ideal weight [300]. The presence of comorbidities such as hypertension, CAD, dyslipidemia, and type 2 diabetes mellitus, as well as the technical difficulties inherent in the surgical and postsurgical care of obese patients likely contribute to this perception. Obese patients have been shown to have a higher incidence of postoperative thromboembolic disease in noncardiac surgery, and this high risk of thromboembolic disease may demand an aggressive approach to deep venous thrombosis prophylaxis [135]. Contrary to common belief, obesity is not associated with increased mortality or postoperative cerebrovascular accident following CABG [301,302]. However, an increased incidence of sternal and superficial wound infection, saphenous vein harvest site infection, and atrial dysrhythmias has been seen [303-305]. The large, poorly vascularized panniculus, the higher incidence of hyperglycemia in the obese, and the difficulty in wound surveillance may predispose obese patients to wound infection [304]. This is also true in regard to CABG in the geriatric population (>75 years of age) [306]. These findings have been confirmed by another study in which obesity (defined as a BMI >30 kg/m2) was not associated with an increased risk of operative mortality, stroke, renal failure, acquired respiratory distress syndrome, prolonged mechanical ventilation, pneumonia, sepsis, pulmonary embolism, or ventricular arrhythmias [303]. Curiously, despite numerous alterations in respiratory physiology in obese patients, such as increased breathing workload, respiratory muscle inefficiency, decreased functional reserve capacity and expiratory reserve volume, and closure of peripheral lung units, pulmonary complications are comparable to those seen in nonobese patients following CABG [303,304]. This discrepancy may reflect different treatment attitudes from staff in the late postoperative period, with more vigorous pulmonary toilet being performed or more vigilance in enforcing postoperative use of incentive spirometry and early ambulation in patients undergoing cardiac surgery. However, this may not apply to severely obese patients (BMI >35 kg/m2), who were more likely to undergo prolonged mechanical ventilation and have a longer postoperative stay [305]. Indeed, a study including over 24,000 patients in the immediate postoperative period reported infrequent unanticipated major problems with ventilation in the postanesthesia period, but when obesity was complicated by diabetes, renal dysfunction, and, in men age over 60 years, problems with ventilation ensued [307]. A retrospective analysis suggested that off-pump CABG surgery may be of benefit in overweight patients compared to on-pump CABG surgery as far as morbidity and mortality are concerned [308]. However, the vast majority of patients in that cohort (72%) presented with a BMI <30>2, thus the true benefit of off-pump CABG surgery in obese patients remains to be determined.
Congestive heart failure
Congestive heart failure (CHF) is the only common cardiovascular condition increasing in incidence, prevalence, and mortality. Although new therapies have been introduced for its treatment, the overall 5-year mortality for CHF is presently estimated at 50%. Elevated BMI predisposes to CHF by promoting hypertension, diabetes, and CHD, and excess obesity is associated with an increased risk of developing CHF [270,309-312]. It is estimated that risk of CHF increases 5% in men and 7% in women for each increment of 1 unit of BMI. This appears to be a continuous gradient with no evidence of a threshold [310]. Even if obesity is a major risk factor for the development of heart failure, the precise mechanisms of their interaction remain uncertain. Physiologically, a close link has been posited between natriuretic peptides and lipolysis, and natriuretic peptide levels are reduced in the obese state, partly due to altered clearance receptors and peptide degradation [313,314]. Natriuretic peptides have been shown to be important stimuli for lipolysis in humans and similar in potency to catecholamines [315]. Adipose cells express the natriuretic clearance receptor [316].
Interestingly, once the patient presents with CHF, obesity may not adversely affect outcome [317-319]. In fact, among patients with CHF, subjects with higher BMI are at lower risk for death and hospitalization than patients with a "healthy" BMI [317,319-323]. However, preoperative obesity (>140% ideal body weight) may increase morbidity and mortality after heart transplantation [324]. Importantly, percent ideal body weight appears to be a better predictor of morbidity and mortality after heart transplantation than BMI [324]. Nonetheless, further studies are needed to investigate the risks and benefits of weight loss in patients with CHF, since lower body weight is associated with a heightened metabolic state that leads to the cardiac cachexia of severe heart failure and increased mortality. Several lines of evidence have been proposed to explain diminished activation of natriuretic peptides, enhanced protection against endotoxin/inflammatory cytokines, and increased nutritional and metabolic reserve. It has been reported that a state of reduced natriuretic peptide level exists in the obese patient with heart failure [325]. The suggestion that adipose tissue clears B-type natriuretic peptide (BNP) at an increased rate raises the possibility that in obese patients there is early loss of natriuretic-mediated vasodilation, lesser antagonism of the renin-angiotensin system, or loss of natriuretic ability. Fasting and weight loss are known to decrease expression of adipose cellular natriuretic peptide clearance receptors in animals [326]. From a clinical perspective, current guidelines for the management of heart failure provide conflicting directions regarding the prognosis and management of BMI. The American College of Cardiology/American Heart Association (ACC/AHA) heart failure clinical practice guidelines for adults do not directly address the issue of BMI [327], while the European Society of Cardiology recommends weight loss for overweight and obese patients with heart failure even though this recommendation is not supported by data from clinical trials [328]. An analysis from 7767 patients with stable heart failure enrolled in the Digitalis Investigation Group Trial (DIG) reported that higher BMI is associated with lower mortality risk [329]. One must keep in mind that the analysis considers only BMI at the time of enrollment, while data on changes in BMI over time are not available. Thus the findings do not address the impact of weight loss or gain during the study period (37 months). In contrast, preoperative obesity (>140% ideal body weight) may increase morbidity and mortality after heart transplantation [324]. The interrelation between sleep disorders and CVD is a topic of growing interest [330]. The frequency with which obstructive sleep apnea causes left-sided CHF and the mechanisms by which this occurs are not clear. Pulmonary hypertension and right heart disease are expected in obese patients with longstanding and moderately severe hypoxemia, which could be potentiated through CHF. In addition, patients with CHF and/or sleep disorders are at increased risk for fatal arrhythmias, and it is important to consider that obesity may modulate this increased risk.
Arrhythmias
The observation that, "Sudden death is more common in those who are naturally fat than in the lean" has been attributed to Hippocrates [40]. Even in the absence of cardiac dysfunction, weight-stable obese subjects have an increased risk of arrhythmias and sudden death [82,331], and the risk of sudden cardiac death with increasing weight is seen in both genders [272]. In the Framingham study, the annual sudden cardiac mortality rate in obese subjects of both genders was estimated to be about 40 times higher than the rate of unexplained cardiac arrest in a matched nonobese population [272,331]. Specifically, in severely obese men, a 6- and 12-fold excess mortality rate was reported in the 35 to 44 and 25 to 34 year-old age groups, respectively [45].
Prolonged QTc interval was observed in approximately 30% of subjects with impaired glucose tolerance in a report coming out of the National Health and Nutrition Examination Survey cohort (NHANES III) [332], and there was a positive association between BMI and QTc [333]. Although not consistent [140,334,335], the relation between fatness and QTc interval persists even after adjusting absolute QT intervals for heart rate using different formulas (Bazett, Framingham, Fridericia) and by multiple regression analysis [333]. Hence, a prolonged QT interval is observed in a relatively high percentage of obese subjects and the association between abnormal QTc and BMI is most evident in the severely obese [153,333]. Of clinical importance, approximately 8% of patients present with a QTc >0.44 seconds and approximately 2% with a QTc >0.46 seconds [336]. Interestingly, prolongation of QTc interval is associated with visceral obesity in healthy premenopausal women (assessed by CT), independent of obesity and other risk factors [337]. Although the QTc may not be extremely increased [approximately 440 ms] in the obese population [334,336], it is important to emphasize that screening for prolonged QT in obesity may suffer from stringent criteria, since a prolongation of QTc for more than 420 ms may be predictive of increased mortality in a healthy population followed for 15 years [338]. Although, abnormal QTc has been shown in other insulin-resistant states often associated with obesity, such as hypertension and diabetes [332], there is no report available describing specific ECG abnormalities (except for cardiomyopathy and rhythm disturbances) in lipodystrophy [339]. Also, the polycystic ovary syndrome has not been associated with either increased QTc interval or QT dispersion [340]. However, most of the subjects with the polycystic ovary syndrome are lean women [340]. Since QT dispersion has been reported as increased in obesity without improvement following weight loss, visceral obesity may be a better discriminant to evaluate the impact of weight loss on QT dispersion [341]. Interestingly, QT dispersion may be comparable in age- and sex-matched controls when obese subjects are not afflicted with the comorbidities often associated with obesity [342], and QT dispersion was reported to be normal in overweight patients with coronary artery disease compared to normal weight patients [140]. Metabolic variables may be of significance in explaining increased QTc interval in obesity. In a model where the QTc interval was the dependent variable and changes in waist-to-hip ratio, BMI, plasma free fatty acids (FFA), epinephrine, norepinephrine, and glucose levels were the independent variables, it was reported that the mathematical model explained approximately 70% of the variance in the QTc interval changes [341]. When visceral obesity or insulin levels increase, sympathovagal balance may be the best explanation for changes in QTc and QT dispersion [343]. The occurrence of small high-frequency ECG potentials (1 to 20 µV) at the end of the QRS complex and into the ST segment is also associated with increased risk for ventricular arrhythmias and sudden cardiac death [344].
The occurrence of late potentials using signal-averaged electrocardiography (SAECG) in a group of obese individuals without clinical heart disease was evaluated [345]. The prevalence and number of abnormalities increased with increasing BMI. In patients with a BMI of 31 to 40 kg/m2, 35% of subjects had abnormal late potentials, whereas in the subgroups with BMIs of 41 to 50 kg/m2 and >50 kg/m2, 86% and 100% of subjects had abnormalities, respectively [345]. Significantly, these abnormalities were found in obese patients irrespective of whether they were hypertensive or diabetic. The presence of late potentials may be facilitated by pathologic myocardial changes associated with obesity (myocyte hypertrophy, focal myocardial disarray, fibrosis, fat, and mononuclear cell infiltration).
The clinical significance of obesity-associated QT prolongation and the mechanisms producing it remain speculative. However, it is interesting to note that elevated FFA may affect cardiac repolarization. This may in part be secondary to increased levels of plasma catecholamines [341,346]. Clinically, a correlation between the levels of long-chain saturated fatty acids and the occurrence of ventricular arrhythmias in patients with myocardial infarction was reported in a univariate analysis [347]. Moreover, by reducing nitric oxide availability, high glucose concentrations may promote increased vasomotor tone and ventricular instability [348,349]. Also, because extremely obese patients often have a dilated cardiomyopathy, arrhythmias may be the most frequent cause of death [82,96]. Nevertheless, all these abnormalities do not infer a cause and effect relationship between the increased risk of arrhythmias and sudden death and increasing weight. The autonomic nervous system makes an important contribution to the regulation of both the cardiovascular system and energy expenditure, and it is assumed to play a role in the pathophysiology of obesity and related complications [40,350]. Numerous approaches, e.g., heart rate variability (HRV), microneurography, and catecholamine turnover, have been employed to study the variation in the autonomic nervous system induced by diet and weight change in humans. However, the roles of the sympathetic and the parasympathetic nervous systems in obesity and weight loss remain to be elucidated. According to Peterson et al [350], both parasympathetic and sympathetic activity decrease as the percentage of body fat increases. These results contrast with other studies which have used more invasive techniques to demonstrate that obesity is associated with predominantly sympathetic activation [351].
Discrepancies between studies on the impact of the autonomic nervous system on obesity can be explained in part by the techniques used to evaluate the autonomic nervous system [352]. Obesity and the 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 [353]. Fluctuation of heart rate (HRV) around mean heart rate provides valuable information on the activity of the cardiac autonomic nervous system. It has been demonstrated that a weight loss of 10% in severely obese patients is associated with significant improvement in cardiac modulation by the autonomic nervous system [354]. This translates into decreased heart rate and an increased HRV, mainly through an increment in cardiac parasympathetic modulation. The reductions in vagal activity observed with increments in weight gain may be one cause of the arrhythmias and other cardiac abnormalities that accompany obesity. Indeed, higher heart rate is associated with increased mortality [355,356], and decreased HRV is associated with increased cardiac mortality independent of ejection fraction [357].
BENEFITS AND RISKS OF WEIGHT LOSS
The general goals of weight loss and management are basic: to prevent further weight gain, reduce body weight, and maintain a lower body weight indefinitely. Patients should have their BMI and level of abdominal fat measured with weight reduction goals established to favorably impact outcome, including cardiovascular health. Obesity management and treatment can include counseling, diet, exercise [358], pharmacotherapy, and surgery. In the obese patient who smokes, smoking cessation is mandatory. However, a major obstacle to smoking cessation has been the attendant weight gain observed in about 80% of quitters [359-361]. The weight gain that accompanies smoking cessation has been quite resistant to most dietary, behavioral, and physical activity interventions. Importantly, though, the weight gain associated with smoking cessation is less likely to produce negative health consequences than continued smoking [6].
Weight reduction depends on energy intake being less than energy expenditure. The energy density of diet is important in this respect. In general, foods high in fat (≥9 kcal/g) and sugar are energy-dense. Thus, diets designed for weight reduction should be restricted not only in total calories but in fat and sugar as well. Approximately 1 lb per week can be lost with no change in physical activity if 500 kcal/d is eliminated. Such a diet would continue to include foods that are low in saturated fat and cholesterol but enriched in nutrients that are associated with a reduced risk for cardiovascular disease, e.g., fruits, vegetables, legumes, and whole grain products. An intervention combining behavioral therapy, a low-caloric diet, and increased physical activity provides the most successful therapy for weight loss and weight maintenance. In overweight and obese patients psychologically ready for weight loss, this approach should be emphasized and sustained for at least 6 months before pharmacotherapy is considered.
Intentional weight loss in obese patients can diminish or prevent many of the obesity-related risk factors for CHD [12,362]. Cardiovascular healthcare professionals must understand the clinical impact of weight loss and be able to implement appropriate weight-management strategies that induce a negative energy balance in obese patients. Behavior modification to enhance dietary and activity compliance is an important component of all of these treatments-counseling, diet, exercise, pharmacotherapy, and surgery. Several modalities have been addressed recently by the AHA [12]. At present, the choice of therapeutic intervention does not appear relevant to the benefits of weight reduction for the cardiovascular system, with a few exceptions to be noted below.
Surgically induced weight loss causes a decrease in resting oxygen consumption and cardiac output that is proportional to the magnitude of the loss in weight [88,363]. Stroke volume falls in parallel to the decrease in blood volume and heart volume. Systemic arterial pressure declines, but systemic arterial resistance changes little, if at all. Left ventricular stroke work diminishes. Pulmonary capillary wedge pressure tends to decrease but may still remain higher in relation to cardiac output compared to normal weight subjects. Left ventricular dysfunction may persist most strikingly during exercise [88].
In overweight subjects, at any given cardiac output, all right heart pressures tend to be higher than in normal weight subjects [88], with relative increases in left ventricular end-diastolic pressure [81]. Table 6 lists the benefits of weight loss for the cardiovascular system. Even if weight loss produces a reduction in left ventricular mass, only between 14% to 25% of that reduction can be explained solely by the change in body weight [364,365]. Perhaps the most important variable in weight loss-induced reduction of left ventricular mass is the reduction in blood pressure and associated neurohormones. Sympathetic mechanisms have been implicated in the development of LVH [145], and weight reduction in obese subjects reduces such indices of sympathetic activity as plasma norepinephrine levels and urinary norepinephrine excretion. The renin-angiotensin system may also be involved in the pathogenesis of LVH, and weight reduction may diminish plasma renin activity and aldosterone levels [366]. Improvement in hyperinsulinemia may also be related to the reduction in left ventricular mass in hypertensive obese subjects, since insulin resistance is an important independent contributing factor to left ventricular mass in normotensive nondiabetic obese subjects [367]. The mechanism explaining the association between LVH and insulin resistance is not known, but one can speculate that hyperinsulinemia plays a role as a growth factor since septal hypertrophy of the heart has been found to occur more frequently in newborn infants of mothers with diabetes. Nonetheless, the role of all these neurohumoral factors in the regression of cardiac hypertrophy associated with weight reduction deserves further investigation. Further research is also needed to produce more evidence of the impact that visceral obesity has on the cardiovascular system [164,230-232,259,341,369,370]. A reduction in angiotensin-converting enzyme activity after weight reduction could also be important [371].
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TABLE 6. Benefits of weight reduction on the cardiovascular system |
ECG changes in the course of weight loss in obese patients appear to be common. However, histologic findings in the hearts of patients dying while ingesting liquid modified protein diets and a group of cachectic patients dying from malignant disease were similar [155], despite absence of ECG abnormalities in the latter and QT prolongation in the former. Thus, the mechanism underlying these ECG changes and the clinical significance of obesity-associated QT prolongation in particular remain speculative. Also, a variety of arrhythmogenic factors have been implicated: acute heart failure with stretching of the myocardium that decreases the electric threshold in myocytes and facilitates spontaneous depolarization; myocyte hypertrophy and multiple intercalated discs that may facilitate the current flow and cause reentrant arrhythmias and increased myocardial oxygen demand; and impaired vasodilatory reserve that may cause acute myocardial ischemia in the absence of coronary artery disease. Although possible, fatty infiltration of the myocardium is not likely to be involved in the majority of cases. Weight loss through different modalities, i.e., starvation [150,152], liquid protein diets [154,155], very low calorie diets, and even obesity surgery [95], has been associated with prolongation of the QTc interval.The prolongation of the QTc interval is independent of the biological and nutritional value of the constituent protein in, or the addition of mineral and trace supplements to, the diet [154]. Most importantly, liquid protein diets that have been associated with potentially life-threatening arrhythmias only become suspect following 24-hour Holter recording [372]. Ventricular tachycardia (torsades de pointes) and fibrillation, refractory to lidocaine, propranolol, phenytoin, mexiletine, disopyramide, and procainamide, have been documented in subjects who died under observation [150,154,373]. Even alternative treatments, i.e., infusion of potassium, calcium, magnesium, bicarbonate, glucagon, and even ventricular overdrive pacing or open chest cardiac massage, were ineffective in controlling the refractory arrhythmia [95,154]. These diets are still in use today. However, it has been reported that effective weight loss using a liquid protein diet may decrease QT dispersion [374]. 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 in the United States in 1997 following reports of an association with cardiac valve disorders [375], particularly aortic and mitral insufficiency. Valve involvement in these patients was histopathologically similar to that noted in the carcinoid syndrome or ergotamine-induced valve disease [376,377]. The development of valvulopathy correlated strongly with duration of exposure [378]. An increased risk of primary pulmonary hypertension was also documented [379-382]. Interestingly, no cases of cardiac valve abnormalities associated with the use of phentermine alone were reported [383], and regression of valvular disease after cessation of fenfluramine and dexfenfluramine has been described [384-386]. The most concerning abnormality seen is aortic regurgitation, which is usually mild [384,387-389] if present at all [390]. This finding appeared to be more significant in patients who took fenfluramine or dexfen-fluramine for more than 3 months [368,387,388]. Since improvement in valvular regurgitation may take place, surgical referral for valve repair and/or change can be delayed [368,388].
Sibutramine hydrochloride and orlistat are the latest drugs available on the market for the treatment of obesity and have been shown to effectively treat obesity and its associated comorbidities [391,392]. Sibutramine hydrochloride, a centrally acting drug [393] which is approved for long-term use, has not been associated with valve abnormalities [394,395]. However, increases in blood pressure and heart rate may occur with the use of this drug [395,396], and, like phentermine, sibutramine should not be used in patients with untreated hypertension, CHD, CHF, arrhythmias, or stroke [393]. The impact on heart structure and function of the endo-cannabinoid receptor antagonists in the treatment of obesity is not known.
CONCLUSIONS
Health service usage and the medical costs associated with obesity and related diseases have been increasing and will continue to increase dramatically [397]. Abdominal obesity as assessed by waist circumference (independent of ethnicity, gender, smoking status, and age) is associated with increased total health care expenditure, especially with the cost of inpatient care [398]. Although medication costs for cardiovascular disease and diabetes mellitus have been shown to be lower in surgically treated obese patients, other medication costs related to the side effects of surgery may increase [399,400]. However, the initial cost of bariatric surgery can be amortized over 3.5 years [401]. Nonetheless, increased physical activity early in life may become the cost effective nonpharmacological avenue in combating obesity [402]. Because of the increased metabolic demand induced by excess body weight [80], at any level of activity the cardiac workload is greater for obese subjects. Nevertheless, the recommendation to increase physical activity needs to be heeded, with advice from a clinician experienced in exercise therapeutics.
It is very important to inform patients about the results to be expected from treatment, to avoid unrealistic weight loss expectations. Body weight normalization should not be the primary target, but rather some weight loss should be the goal, which can lead to substantial improvement in the risk factor profile [403]. Aside from an enhanced metabolic profile, weight loss impacts favorably on the cardiovascular system through multiple 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 to lean poorly fit subjects [404]. 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 attempt intentionally to lose weight present significantly lower all-cause mortality, independent of weight change [405-407].
In this regard, intentional weight loss (from 33.5 to 27.7 kg/m2) has been associated with a 25% reduction in mortality in overweight patients with diabetes [407]. Obesity is a chronic metabolic disorder associated with CVD and increased morbidity and mortality. When the BMI is ≥30 kg/m2, mortality rates from all causes, and especially cardiovascular disease, are increased by 50% to 100%. It is clear that a variety of adaptations and 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 demands, 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 dilation of these cardiac cavities, increasing wall tension. This leads to LVH, which, in turn, 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 dilation, wall tension increases even more and systolic dysfunction may ensue. Systemic hypertension, pulmonary hypertension (left ventricular failure, chronic hypoxia), and CHD all occur at disproportionately high rates 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. There is strong evidence that weight loss in overweight and obese individuals reduces risk factors for diabetes and cardiovascular disease. Additional evidence indicates that weight loss and the diuresis associated with it reduces blood pressure in both overweight hypertensive and nonhypertensive individuals, reduces serum triglyceride levels and increases high-density lipoprotein cholesterol (HDL-C) levels, and may produce some reduction in low-density lipoprotein cholesterol (LDL-C) levels. Weight loss also reduces blood glucose levels and hemoglobin A1c levels in patients with type 2 diabetes and diminishes signs and symptoms of left ventricular failure and obstructive sleep apnea.
Finally, beside the metabolic abnormalities associated with obesity, the obese state impacts the cardiovascular system unfavorably and increases the burden on the heart structurally and functionally. Thus, to achieve better prevention and effective intervention, the obese individual should be evaluated from both the metabolic and the cardiovascular standpoint. It is to be hoped that within the next decade new data will be gathered that shows weight reduction to be beneficial for hard CVD outcomes, i.e., CHD events, CHD death, CHF, stroke, and total mortality. Until then, the clinical approach must be based on the hope that such favorable results will ensue. Overweight and obesity have been identified as major CVD risk factors since 1998, and, although we understand, to some extent, the pathophysiological link between overweight and obesity and many forms of CVD, a number of scientific questions remain to be addressed.
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