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Hypertension occurs more commonly in obese than in lean persons at virtually every age. A variety of endocrine, genetic, and metabolic mechanisms have been linked to the development of obesity hypertension. These include insulin resistance and hyperinsulinemia, increased serum aldosterone levels, salt sensitivity and expanded plasma volume in the presence of increased peripheral vascular resistance, a genetic predisposition, and possibly increased leptin levels. Pressure and volume overload are present in obese hypertensives. This leads to a mixed eccentric-concentric form of left ventricular hypertrophy and increases the predisposition to congestive heart failure. Weight loss, even in modest decrements, is effective in reducing obesity-hypertension, possibly by ameliorating several of the proposed pathophysiologic mechanisms. There are currently no specific recommendations concerning pharmacotherapy of obesity-hypertension because each drug group has pros and cons.
and may be defined as weight 20% above ideal body weight. However, because obese persons have an increased fat-free mass compared with lean persons of the same height, the use of an “ideal” body weight to determine obesity may be misleading. Under the current uniform measure for obesity, body mass index (BMI), obesity is defined as having a BMI greater than 27.8 kg/m2 for men and 27.3 kg/m2 for women.
However, the literature is divergent on the prevalence of hypertension in the obese. The Second National Health and Nutrition Examination Survey (NHANES II) data offer a possible explanation for this variability.
Even though overall data showed that obese persons were 3 times as likely as nonobese persons to have hypertension, there were differences among individual groups. For example, obese young adults had a 5.5-fold higher risk than older obese, whereas the risk was only 1.9 times higher in those between the ages of 45 and 75 years. Even though white women had a lower prevalence of obesity, they were at a greater risk for developing obesity-hypertension.
These differences may be related to close association of hypertension to upper-body rather than lower-body obesity. Not surprisingly, upper-body obesity is associated with increased mortality. The presence of hypertension, diabetes mellitus, smoking, and increased levels of lipids modify this increased mortality. In fact, obesity in and of itself contributes very little to the increased risk of mortality.
A series of endocrine, genetic, and metabolic mechanisms have been linked to the development of obesity-hypertension. These include insulin resistance/ hyperinsulinemia, overactivity of sympathetic nervous system, the renin-angiotensin-aldosterone system, salt retention, genetic predisposition, and leptin levels. A schematic review of these mechanisms and their probable interaction in causation of obesity hypertension is presented in Figure 1, and each mechanism is discussed below.
Figure 1Schematic of mechanisms of obesity-hypertension and their probable interactions.
Obesity-hypertension is strongly associated with insulin resistance, which in turn leads to increased insulin levels, especially in those with upper-body obesity. Hyperinsulinemia results from accumulation of lipolytic hyperactive abdominal cells, with release of large amounts of free fatty acids in the portal vein. Excess free fatty acids leads to increased synthesis of triglycerides, which in turn inhibits insulin uptake and causes insulin resistance and hyperinsulinemia.
Additional evidence that upper-body obesity induces hyperinsulinemia derives from the fact that the percentage of body fat and waist-to-hip ratio strongly correlate with insulin’s action on glucose uptake.
The association between high insulin levels and obesity is not uniform. Maxwell et al failed to demonstrate consistently high insulin levels in the obese.
Despite the controversy, there is a general agreement that insulin plays a causative or contributory role in obesity-hypertension.
Renin-Angiotensin-Aldosterone System and Other Endocrine Factors
It has been suggested that the renin-angiotensin-aldosterone system plays an important role in obesity-related hypertension. When measured, however, renin levels are no higher in obese persons than they were in lean subjects. In fact, the renin levels progressively decrease as obesity becomes more severe.
in obese persons, then, there is an increase in the ratio of plasma aldosterone levels to plasma renin levels. This relative increase in the aldosterone leads to a higher total body salt and water and therefore plays a role in the pathogenesis of hypertension in the obese.
Other endocrine factors that potentially play a role in the causation of obesity-hypertension relate to corticosteroids and sympathetic nervous system. Cortisol production and urinary excretion of cortisol are increased in obesity, even though plasma cortisol level is within normal limits.
Increased sympathetic activity, specifically high norepinephrine levels, is associated with increased incidence of hypertension in the presence of obesity. Ward et al
demonstrated a 3.5-fold higher prevalence of hypertension in those in the highest terciles of insulin and norepinephrine levels compared with those in the lowest terciles.
The mechanisms by which obesity induces salt sensitivity and increased salt intake are not well understood. It has been proposed that insulin resistance and hyperinsulinemia play an important role.
In lean subjects with hypertension, blood volume has an inverse relationship to blood pressure: the higher the blood pressure, the lower the blood volume.
High cardiac output may lead to increased blood pressure. In addition, the normal compensatory response of a decrease in PVR in response to increased blood volume is blunted in the obese. In other words, there is a relative increase in the PVR. Hence, both the increased blood volume with resulting increased cardiac output and a relative increase in PVR contribute to obesity-hypertension. Further investigation on the subject has shown that intracellular body water is increased more than interstitial fluid volume and plasma fluid volume.
The increased intracellular-to-interstitial fluid volume ratio may be related to increased intracellular water or decreased interstitial water or combination of these factors. How or whether it contributes to causation of hypertension remains speculative.
Leptin
Leptin is a 167-amino-acid hormone secreted by adipocytes. It decreases caloric intake by interacting with leptin receptors in the hypothalamus.
However, its role in obesity-hypertension in humans is controversial. Some investigators were able to demonstrate a relationship between obesity-hypertension,
To further confound the issue, administration of leptin can lead to opposing effects on hypertension; although long-term administration may increase sympathetic activity with resultant pressor effects,
Thus, the role of leptin in causation of obesity-hypertension, if any, is not clear.
Genetics
That genetics may be important in causation of obesity-hypertension is derived from the facts that central obesity is caused in part by genetic predisposition
Also, high blood pressure is not consistently seen with obesity, and it is likely that the blood pressure response to obesity may be influenced by genetic background.
failed to document association between the ob gene locus and hypertension, at least in African Americans. This is a relatively new area of inquiry and more work is undoubtedly ongoing.
Obesity-Hypertension and The Heart
Because of the high blood volume in the obese, venous return to the right atrium, preload to the left atrium, left ventricular (LV) filling pressure, LV volume, and cardiac output are all shown to be increased.
In essential hypertension (without obesity), the total PVR is increased, resulting in an accentuated afterload and LV wall tension. Contractile elements are added in parallel, leading to thickening of the chamber wall, which in turn leads to diminished chamber volume.
As opposed to this concentric hypertrophy seen with essential hypertension, obesity (without hypertension) causes “eccentric” LV hypertrophy. The eccentric hypertrophy is the result of increased LV preload, resulting in chamber dilation and increased wall tension. The LV adapts to it by adding contractile elements in series (as opposed to parallel in the case of nonobese essential hypertension). The result is eccentric LV hypertrophy.
Other potential factors involved in the pathogenesis of LV hypertrophy include demographics (age, sex, race), exogenous intake (salt and alcohol), and neurohumoral (insulin- like growth factor, angiotensin, sympathetic activity) factors. Diagrammatic representation of these cardiopathies is depicted in Figure 2, and a unifying pathogenetic scheme is shown in Figure 3.
Figure 2Left ventricular cavity size and wall thickness in lean normotensive, obese normotensive, lean hypertensive, and obese hypertensive patients.
LV hypertrophy can increase the hemodynamic burden on the heart and predispose the patient to the development of heart failure. Accordingly, eccentric hypertrophy associated with obesity without hypertension,
are all associated with increased risk of developing congestive heart failure.
LV hypertrophy affects coronary circulation, causing relative myocardial ischemia during periods of increased demand, and ultimately coronary artery disese.
Explanation for these arrhythmias derives from autopsy studies on obese subjects. One study documented mononuclear cell infiltration in and around the sinoatrial note and/or its approaches, with marked fat throughout the conduction system;
They demonstrated that sodium retention at the level of loop of Henle that may be caused by insulin resistance and hyperinsulinemia, increased sympathetic activity, activation of renin-angiotensin-aldosterone system, and/or higher renal interstitial fluid hydrostatic pressure. Microscopic examination of the animal kidneys revealed an increase in the interstitial cells and expansion of the extracellular matrix between tubules in the renal medulla. They concluded that obesity-hypertension is associated with a shift of pressure natriuresis toward a higher blood pressure. Similar morphological changes in kidneys of obese humans are described in an autopsy series.
proposed that the renal alterations seen with obesity are caused by increased filtration fraction and increased intraglomerular pressure. He also implicated salt sensitivity along with increased salt retention, increased sympathetic activity, and insulin resistance and hyperinsulinemia (Figure 4). In both obese and nonobese subjects, increased blood pressure is associated with a higher albumin excretion.
This reduction in blood pressure is seen whether or not salt restriction is instituted at the same time. Modest reduction in weight (5 to 10 kg) was effective in up to 75% of the subjects. In addition to better blood pressure control, weight loss is associated with reduction of insulin levels, sympathetic activity, possibly renin and aldosterone levels, and intracellular sodium levels. Cardiac benefits of weight loss manifest in decrease in the interventricular septal thickness, posterior wall thickness, and total LV mass. However, weight reduction is not always an easy goal to attain, and most weight-loss programs report dropout rates of 50 to 70%. Lifestyle change is recommended and may be more successful.
Antihypertensive Medications
Pharmacological therapy should be reserved for those with obesity-hypertension who have moderate to severe hypertension and who are unable/unwilling to lose weight and/or modify lifestyle.
The goal of treatment is to reduce the cardiovascular risk, and the goal of blood pressure reduction depends on presence of other risk factors as defined by JNC VI.
Any antihypertensive agent could be used for the treatment of obesityhypertension depending on its efficacy, effect on the metabolic profile, and mechanism of action for lowering blood pressure. Unfortunately, information is sparse concerning the use of antihypertensive medication in obese-hypertension. Table 1 provides a summary of experience, sometimes limited, with different classes of antihypertensive agents in the treatment of obesity-hypertension.
Table 1Pharmacologic Treatment of Obesity-Hypertension
Drug Class
Mechanism
Pros
Cons
Thiazide diuretics
↓ Intravascular volume
Effective
Higher doses may be needed. Adverse lipid profile
↓ Cardiac output
β-Blockers
↓ Cardiac output
↓ Norepinephrine Levels; inexpensive
? Efficacy may induce overeating. Adverse lipid profile
Centrally acting sympatholytic agents
Inhibition of epinephrine ↓ Peripheral vascular resistance
Inexpensive; no effect on lipid profile.
Clonidine found not to be effective at a dose of 0.4 mg/day.
α 1 blocking agents
↓ Peripheral vascular resistance
Improved insulin sensitivity and lipid profile
Large or long-term studies not available.
Dihydropyridine calcium channel antagonists
↓ Peripheral vascular resistance
Effective; better glucose tolerance and less insulin resistance.
Expensive; individual responses vary.
↓ Cardiac output Natriuresis
Angiotensin-converting enzyme inhibitors
↓ Peripheral vascular resistance
Effective in whites and younger patients; improved insulin sensitivity.
Expensive; not effective in blacks and older subjects; limited experience in obesity
Several epidemiological studies have demonstrated a direct relationship between central obesity and hypertension. A series of endocrine and metabolic mechanisms have been linked to the development of obesity-hypertension. These include insulin resistance, hyperinsulinemia, increased adrenergic activity and aldosterone levels, and increased salt and water retention. Low levels of leptin and genetic predisposition may also be important. Hemodynamically, the cardiac output is increased with relatively little change in PVR. These changes cause eccentricconcentric LV hypertrophy that predisposes to congestive heart failure. The risk of arrhythmias and sudden death is increased in obese persons. Glomerular filtration rate and renal blood flow are increased. Hyperperfusion and hyperfiltration can cause glomerulosclerosis. In addition, changes pertaining to increased salt reabsorption and tubular damage caused by urinary proteins are also observed. Weight loss has a salutary effect on each of these complications of obesity. In the presence of moderate to severe hypertension, and when weight loss is not possible, pharmacological therapy may be instituted; angiotensin-converting enzyme inhibitors, calcium antagonists, and β-adrenergic receptor blockers may be used as first-line drugs.
References
Bray G.
Obesity in America. An overview.
in: Bray G.A. Obesity in America. U.S. Department of Health, Education, and Welfare, Public Health Service,
Bethesda (MD)1979: 1-9
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