Extreme Obesity, Surgical Weight Loss, and Cardiovascular Health

| August 10, 2014

by Peter N. Benotti, MD, The Obesity Institute, Geisinger Medical Center, Danville, Pennsylvania.

Severe obesity is a well-known risk factor for atherosclerosis and cardiovascular disease. Obesity is also a defining characteristic of the metabolic syndrome, a group of conditions associated with metabolic dysfunction and cardiovascular risk. The cardiovascular abnormalities that occur as a consequence of extreme obesity and its associated conditions contribute to an increase in all-cause mortality and morbidity as will as reduced life expectancy. This article will summarize the available information regarding the pathophysiology of cardiovascular disease in obesity, the impact of obesity on cardiac structure and function, and the major benefits afforded by surgical weight loss.

Bariatric Times. 2014;11(8):8–11.

FUNDING: No funding was provided.

DISCLOSURES: The author reports no conflicts of interest to the content of this article.

Extreme Obesity and Vascular Disease
Atherosclerosis occurs in association with increases in mediators of systemic inflammation and increases in levels of certain components of the coagulation sequence. Increases in these mediators of systemic inflammation and coagulation also occur in association with the metabolic syndrome.[1] Recent discoveries regarding the endocrine physiology of adipose tissue help to explain the pathogenesis of atherosclerosis, which arises from a combination of systemic inflammation, a procoagulant state, and disruption of normal endothelial homeostasis (Figure 1).

Adipose tissue has been traditionally viewed as a pure storage organ. Recent evidence suggests that the cellular elements of adipose tissue, which include adipocytes, macrophages, pre-adipocytes, lymphocytes, fibroblasts, and vascular cells contribute to the pathogenesis of obesity-related disease by way of the products they synthesize and release.[2] Endocrine products of adipose tissue are collectively termed adipokines, and the adipokine secretory profile is influenced by body mass index (BMI), as well as adipose tissue location.[1,3] Adipocytes express numerous receptors and, as participants in the innate immune response, are capable of responding to infectious or cytokine-mediated inflammatory signals. Endocrine products of adipose tissue that have autocrine, paracrine, or endocrine functions include TNFα, plasminogen activator inhibitor-1, interleukins, leptin, elastin, adiponectin, and others.[1,3] Evidence is accumulating that normal health and metabolism involve a balance in production between those adipokines that promote inflammation and metabolic dysfunction, and those that suppress inflammation and improve metabolic function. Imbalance in adipokine production is felt to be a major mechanism contributing to comorbid conditions and the health risks of obesity, such as cardiovascular disease and possibly cancer.

Diet-induced weight gain results in enlargement of adipocytes and alterations in their capillary circulation, nutrient diffusion distance, and cellular elements.[2,3] Adipose tissue blood flow diminishes with increasing obesity.[4] As the degree of obesity increases, adipose tissue is infiltrated by macrophages and the number of macrophages present in adipose tissue is directly related to adipose tissue mass.[5]  The mechanism for this may be related to adipose tissue hypoxia or ischemia, but the net result is a shift in the balance of adipokine production favoring a pro-inflammatory state.[1-3,6] This state of adipose tissue imbalance or deregulation in severe obesity has been termed adiposopathy.[7] The chronic low-grade systemic inflammation, which characterizes obesity, contributes to metabolic dysfunction and insulin resistance. The extent of inflammatory activity and metabolic deregulation as well as levels of plasminogen activator inhibitor-1 (PAI-1), angiotensinogen II, C reactive protein (CRP), fibrinogen, and TNFα, increase with BMI.[8] The proinflammatory and procoagulant phenotype, which is unmasked in extreme obesity, is also linked to alterations in endothelial homeostasis, which predispose to vascular disease.
Recent evidence indicates that the physiology of adipose tissue varies with the location of the adipose tissue deposits, and that the local adipokine secretion may affect the function of tissue adjacent to the adipose tissue.[1,9] In comparison with subcutaneous adipose tissue, visceral adipose tissue secretes greater amounts of inflammatory mediators, such as TNFα, IL6, plasminogen activator inhibitor-1, angiotensin, platelet activating eicosanoids, and C reactive protein.[1,10] This may be related to release of inflammatory mediators from visceral fat into the portal vein, which up regulates secretion and systemic release. Systemic inflammation and visceral obesity are defining characteristics of the metabolic syndrome, which includes hypertension, hypertriglyceridemia, low HDL cholesterol, and insulin resistance.[11] The metabolic syndrome is an established risk factor for cardiovascular disease.

The vascular endothelium, a continuous single layer of cells at the interface between blood and tissues, is not simply an inert barrier, but an active organ capable of sensing alterations in hemodynamic forces and responding to blood-borne signals. Under basal conditions, the endothelium prevents thrombosis and prevents blood from coming into contact with the thrombogenic sub endothelial tissue. This cell layer maintains a fine balance between forces promoting and those inhibiting thrombosis, vasoconstriction, and inflammation. Continuous modulation of this balance maintains vessels in a partially dilated state preserving vascular patency.[12] Vascular sheer stress is sensed by endothelial cells and results in vasodilatation, mediated by the production and release of nitric oxide. This process is termed flow-mediated dilatation, which can be measured clinically to assess endothelial function, and requires occlusion of the brachial artery with a blood pressure cuff and ultrasound quantification of dilatation of the brachial artery in response to restoration of blood flow.[13]

Normal endothelial function requires the presence of nitric oxide. The pro-atherosclerotic phenotype is unmasked when the endothelial hemostasis is altered, a condition termed endothelial dysfunction or endothelial activation. This condition represents a systemic pathologic state favoring vasoconstriction, coagulation, and inflammation. Inducers of endothelial dysfunction include inflammatory mediators, and other known cardiovascular risk factors, such as insulin resistance, increased LDL, increased cholesterol, smoking, and obesity.[12–14] Nitric oxide, which is the modulator of endothelial homeostasis, is a vasodilator and an inhibitor of monocyte adhesion and platelet aggregation. Endothelial dysfunction, which is usually associated with reduced availability of nitric oxide, promotes the atherosclerotic phenotype.[15]

CRP is a key inflammatory mediator believed to be involved in the initiation and progression of atherosclerosis.[16] CRP is an acute phase reactant, produced by hepatocytes after stimulation by cytokines, particularly interleukin 6 from visceral adipose tissue. Release of this protein occurs as part of the innate immune response. Levels of CRP are increased in obesity and correlate with the severity of the metabolic syndrome. Increased levels of CRP are markers of the chronic low-grade systemic inflammation associated with these conditions. CRP levels have a strong correlation with the risk for cardiovascular events as well as cardiovascular prognosis.[17] This association may be related to the direct effects of CRP on endothelial homeostasis. These effects of CRP that promote atherosclerosis are listed in Table 1.[16,18] In addition, CRP may contribute to a procoagulant environment by inducing monocytes to produce tissue factor and by stimulating endothelial cells to produce PAI-1.[16]

In the presence of inflammatory mediators and other inducers of endothelial dysfunction, LDL cholesterol moves across the vascular endothelium into the sub endothelial tissues. Monocytes bind to and move across the endothelium and oxidize LDL cholesterol. Additional monocytes are attracted and become macrophages in the sub-endothelial tissues where they scavenge oxidized LDL cholesterol. The lipid-laden macrophages become foam cells, which accumulate, and with proliferating smooth muscle cells, form the expanding atherosclerotic plaque. As oxidized LDL accumulates in the arterial wall, chemo attractants are released and leukocytes, inflammatory macrophages, and T cells accumulate. These activated cells release proteolytic enzymes and other substances, which alter the structural matrix and contribute to instability of the growing plaque. Rupture of the unstable plaque exposes the circulating blood, already in a procoagulant condition as a result of disruption of endothelial homeostasis and systemic inflammation, to the subendothelial tissues, which are a source of tissue factor. The result is vascular occlusion that usually produces a clinical catastrophe[19] (Figure 2).

Extreme Obesity and the Heart
Since the early years of bariatric surgery, cardiologists have carefully studied the heart in patients with extreme obesity and have described a consistent pattern of alterations in cardiac structure and function, which occur with progressive severe obesity. Extreme obesity is associated with an expanded fat and lean body mass, which result in increased metabolic demands and oxygen consumption. Augmented blood flow is required to perfuse the expanded body mass. At any level of physical activity, cardiac output is increased and systemic vascular resistance is decreased in normotensive severe obesity. The increased cardiac output is generated by an expanded plasma volume and increased preload which increases stroke volume and stroke work. The increased preload causes increases in end diastolic pressures and volumes. The enhanced stroke work causes dilatation of the ventricular cavity and increasing wall tension. In order to compensate for this and maintain systolic performance, the left ventricle increases its muscle mass, a process called eccentric hypertrophy. Left atrial enlargement may also occur as a response to the augmented plasma volume, and this may explain the association of atrial fibrillation with obesity.[20]

When systemic hypertension complicates obesity, cardiac work (the product of stroke volume and ventricular pressure) is increased and ventricular hypertrophy is enhanced. In extreme obesity, cardiac weight has a linear relationship to body weight. In the setting of cardiac hypertrophy, cardiac function is adversely affected by the alterations in chamber size and shape and ventricular function gradually declines. The initial functional alteration is impaired diastolic filling of the left ventricle, referred to as diastolic dysfunction.[4] The hypertrophied left ventricular wall is stiff with reduced compliance causing impairment in diastolic filling. Longer durations of obesity result in diminishing systolic performance perhaps related to coronary artery disease with limitations in blood flow to the sub-endothelium resulting in myocardial fibrosis or, possibly lipotoxity related to the accumulation of myocardial fat.[21] Extreme obesity is a major cause of congestive heart failure and heart failure resulting largely from extreme obesity is termed obese cardiomyopathy.[22]

When obstructive sleep apnea and/or obesity hypoventilation complicate extreme obesity, the associated hypoxemia, acidosis, and pulmonary hypertension will further worsen cardiac function and predispose to right ventricular failure (Figure 3).

Surgical Weight Loss and the Cardiovascular System
The beneficial effects of intentional weight loss on coronary artery disease risk is well known in the medical community from earlier results of medical weight loss trials.[4,23] Recent evidence suggests that the greatest incremental benefit in cardiovascular risk parameters occurs with weight loss following bariatric surgery.[23] There is also substantial evidence confirming improvement in the structure and function of the heart following surgical weight loss[4,22,23] and more limited information documenting improvement in atherosclerotic load.[24,25]

The reduction in body mass, which accompanies surgical weight loss, reduces metabolic demands, resulting in a decrease in oxygen consumption and cardiac output. Stroke volume decreases as plasma volume and heart volume also decrease. Systemic arterial pressure declines as does stroke work. Pulmonary artery pressures, including pulmonary capillary wedge pressures decline. These physiologic improvements are accompanied by favorable cardiac anatomic remodeling as numerous studies have demonstrated reductions in left ventricular mass and improvements in cardiac chamber geometry, which translate to improvements in systolic and diastolic function. These improvements in cardiac structure and function are accompanied by significant improvement in functional status and cardiopulmonary symptoms.[4,22,23]

In addition to weight loss, postulated mechanisms for these favorable anatomic and physiologic changes include reduced sympathetic activity, reduced blood pressure, improved insulin sensitivity, and reduced plasma renin and aldosterone levels, which accompany surgical weight loss.[4,23]
In addition to improvement in obese cardiomyopathy, surgical weight loss is also associated with loss of visceral adipose tissue,[26] improved endothelial function,[27] a reduction in levels of inflammatory mediators,[28] and restoration of more normal metabolism.[29] Increasing evidence points toward bariatric surgery as a powerful tool that has the potential to resolve the adiposopathy associated with severe obesity.[7] These favorable changes in the pro-atherosclerotic profile are felt to contribute restoration of more normal endothelial homeostasis, improvement in systemic inflammation, and reduced procoagulant activity, all of which favorably affect the progression of atherosclerosis. Surgical weight loss has been shown in a number of studies to reduce the levels of CRP, IL 6, PAI-1, endotoxin, and leptin.[23,30] These changes correlate with the restoration of more normal metabolic function.[29]

Adiponectin is a peptide hormone produced by adipocytes, which has a role in enhancing insulin sensitivity, and in cardiovascular health. High levels of this hormone are associated with vascular health and a decreased risk of myocardial infarction. Levels of this hormone are reduced in extreme obesity and diabetes. They have an inverse relationship to levels of inflammatory markers and are restored toward normal after surgical weight loss.[2,30]

The normalization of adipose tissue secretory products and improvement in endothelial homeostasis after bariatric surgery are major contributors to the documented improved cardiovascular health after surgical weight loss. Several noninvasive vascular imaging studies have demonstrated favorable effects of bariatric surgery on imaged atherosclerosis.[24,25]

The metabolic and physiologic changes associated with extreme obesity, and their resolution or improvement as a result of surgical weight loss are the postulated mechanisms for the numerous clinical studies thath have confirmed the beneficial effects of weight loss surgery on cardiovascular health.[31] It is also quite possible that signaling and endocrine communication from adipose may play a significant role in the pathophysiology of many other health risks and comorbid conditions associated with extreme obesity. Assessment of pro- inflammatory activity in adipose tissue may have a future role in risk assessment in the management of extreme obesity.

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