Pathophysiology and treatment of obesity‐related hypertension

Abstract

The prevalence of overweight and obesity has increased significantly in the United States and worldwide. Among the many complications of obesity, hypertension is the most common and major one accounting for about 70% in the obese subjects. However, the pathophysiologic factors of obesity‐related hypertension and its therapeutic options are not well understood at present. To better understand the pathophysiology of obesity‐related hypertension and its treatment options, a Medline search of the English language literature was contacted between 2010 and 2018 and 22 pertinent papers were selected. The information from these papers together with collateral literature will be discussed in this review.

1. INTRODUCTION

Overweight and obesity in both children and adults have increased significantly in the United States and worldwide and are bound to become a major epidemic with significant economic, social, and health consequences.1, 2 In the United States alone, the prevalence of obesity in adults has increased from 30.5% between 1999 and 2000 to 39.6% between 2015 and 2016, and is projected to reach 2.1 billion people worldwide by the year 2030.3 Obesity is also a major risk factor for cardiovascular disease (CVD), coronary heart disease (CHD), type 2 diabetes mellitus (T2DM), heart failure (HF), and hypertension, which accounts for about 70% among its complications.4 However, the pathophysiologic mechanisms leading to obesity‐related hypertension are not clear at present and several factors have been proposed for its development, such as the leptin, the sympathetic nervous system (SNS), the renin‐angiotensin‐aldosterone system (RAAS), the natriuretic peptide (NP) system, and the renal compression from the excess accumulation of intra‐abdominal and retroperitoneal fat. Understanding the role of these factors in the pathogenesis of obesity‐related hypertension is very critical for the successful treatment of hypertension of obese subjects. For this reason, a Medline and EBAY search of the English language literature was conducted between 2010 and 2018 and 22 pertinent papers were selected. The information from these papers together with collateral literature will be discussed in this review.

2. FACTORS IMPLICATED IN THE OBESITY‐RELATED HYPERTENSION

Despite the ubiquity of hypertension in obesity, its pathogenesis is not well known at present, and several factors have been proposed, among which are the leptin, the SNS, the RAAS, the NPs, and the renal compression.4, 5, 6, 7 All these factors are summarized in Table 1, and their function is depicted in Figure 1, and they will be discussed briefly in the following sections.

Table 1.

Factors involved in the pathogenesis of obesity‐related hypertension

Factor	Action
Leptin	Suppresses appetite, causes early satiety, decreases food intake, lowers body weight, and decreases insulin resistance, leading to lower BP
SNS	Obesity is associated with increased sympathetic and decreased parasympathetic activity. These actions lead to peripheral vasoconstriction, increase in peripheral vascular resistance and increase in BP
RAAS	Adipocytes contain AGT and exert their paracrine action by the local production of Ang II through independent pathways, and by the local release of aldosterone. They also have aldosterone receptors. These actions mediate the BP rising effects of RAAS
NPs	NPs have potent diuretic, natriuretic and lipolytic effects, but their plasma levels are depressed in obesity. Exercise, weight loss and neprilysin inhibitors increase their plasma levels
Renal compression	Increase in intra‐abdominal and retroperitoneal fat causes renal compression, increases intrarenal pressure, decreases sodium excretion and stimulates the RAAS

NPs, natriuretic peptides; RAAS, renin‐angiotensin‐aldosterone system; SNS, sympathetic nervous system.

Figure 1.

Factors involved in the pathogenesis of obesity‐related hypertension. The figure demonstrates the interplay of AGT, Ang II, Leptin, sympathetic nervous system, and natriuretic peptides, leading to increase in peripheral vascular resistance from one side and the cardiac output from the other site, the combination of which leads to increase in BP. Adapted with permission from Engeli et al7

2.1. The leptin factor

Leptin is a 16‐KDa adipokine, which plays a significant role in the regulation of body weight and obesity‐related hypertension. Increased levels of leptin are associated with loss of appetite, increased satiety, and decreased weight gain.6 In contrast, mutations of the human leptin gene, or global deficiency of leptin (Ob/Ob), or leptin receptors (Db/Db) results in hyperphagia, weight gain, and obesity, but not hypertension as has been shown experimentally in mice, indicating that leptin and leptin receptors are necessary for the development of hypertension.8 There is also a gender difference in leptin levels with females having higher levels of leptin and leptin receptor (ObR) expression than males.9 With respect to leptin production, the subcutaneous adipose tissue produces more leptin than the visceral adipose tissue and since subcutaneous adipose tissue is more predominant in females, this difference may account for the higher levels of leptin in women than men.10 Also, leptin exerts its effects on BP through stimulation of hypothalamic leptin receptors including the melanocortin 4 receptors (MC4R) and male mice deficient in MC4R do not develop hypertension despite severe obesity and hyperleptinemia, suggesting that this signaling pathway is crucial in the development of leptin‐mediated hypertension,6 There is also, an association between plasma levels of leptin and hypertension in both men and women.11, 12 Asferg et al11 showed this in 920 patients who were normotensive initially, and 254 who developed hypertension later, had increased leptin levels and demonstrated a significant association between leptin and BP levels, odds ratio (OR) 1.28 (95% CI: 108‐1.53, P < 0.005). There was no association of adiponectin with the incidence of hypertension as expected, since adiponectin stimulates the release of leptin and NPs and prevents weight gain. In another study, Shankar and Xiao showed in 5599 hypertensive subjects ages 40‐48 years, a dose‐response relationship between the plasma levels of leptin and BP, and these effects of leptin were independent of age, sex, and BMI.12

2.2. The SNS factor

Overactivity of the SNS is a common feature of obesity in both animal and human models, and plays an important role in the obesity‐related hypertension.13 In obesity, generally there is an increase in sympathetic and a decrease in parasympathetic activity, and weight reduction has the opposite effects as assessed by direct recordings of muscle sympathetic nerve activity (SNA) and norepinephrine spillover.6 The SNA could lead long term to hypertension through peripheral vasoconstriction, increase in peripheral vascular resistance, and increase in renal tubular sodium reabsorption in both animal and human models.14 Experimentally, in hypertensive animal models, it has been shown that chronic sympathetic stimulation leads to a reset in higher levels of renal pressure natriuresis with decreased sodium and water excretion accounting for the development of hypertension.14 In addition to SNA and the action of norepinephrine, there is also, increased vascular production of endothelin‐1 in obese patients contributing to the obesity‐related hypertension and blockade of endothelin type A (ET_A) receptor leads to reduction of BP.15

2.3. The RAAS factor

The RAAS has also been shown to play an important role in the pathogenesis of obesity‐related hypertension in both men and women.6, 16, 17 Obese hypertensive patients with increased visceral fat have increased angiotensinogen (AGT), levels, plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone levels despite the volume expansion and hypertension.18 In addition, there is evidence for the action of mRNA and the gene that encodes renin and the enzymes cathepsin D and G, which produce Ang I and Ang II through alternative pathways, and also, of higher expression of renin receptors in the visceral than the subcutaneous adipose tissue accounting for the sexual difference in the prevalence of hypertension.19, 20 The long‐term increased activation of RAAS could cause renal injury through constriction of the efferent arteriole via increase in the intraglomerular pressure leading to nephron loss and decrease in the excretion of sodium and water. Clinical trials have supported this concept by antagonizing the RAAS with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers.21 Also, besides the renin receptors, there is evidence of a mineralocorticoid receptor and of the role of aldosterone in obesity‐related hypertension, which provides important therapeutic options for the treatment of obesity‐related hypertension and the prevention of target organ damage.6

2.4. The natriuretic peptide factor

The NPs consist of the atrial natriuretic peptide (ANP), the brain natriuretic peptide (BNP), and the C‐type natriuretic peptide (CNP), which are produced by many tissues, including the brain, the kidney, and mainly the heart, and play an important role in the body cardiovascular and electrolyte homeostasis.7, 22, 23 They are encoded by a separate gene and exert their vasodilating, diuretic, natriuretic, and lipolytic actions through their membrane receptors.22, 23 The human genes for ANP and BNP are located on chromosome 1 and the gene for the CNP on chromosome 2, and exert their cardiovascular and metabolic effects through their receptors, NPR‐A, NPR‐B, and NPR‐C, for the ANP, BNP, and CNP, respectively.22, 23 The ANP and BNP mainly function as cardiac hormones and are excreted from the walls of the atrium and ventricle of the heart through a wall stretching mechanism, whereas the CNP is mainly secreted from the vascular endothelium and causes vascular relaxation, but their usefulness in obesity‐related hypertension is compromised by their low levels and their short half‐lives.24 Their BP lowering effects in obese hypertensive subjects are mediated through their diuretic, natriuretic, vasodilating, and weight reduction properties due to their lipolytic actions.25, 26, 27 Another beneficial effect of NPs is the activation of adiponectin, a hormone that induces leptin release leading to prevention of weight gain, and increase in insulin secretion and sensitivity, important factors for obese hypertensive subjects with the metabolic syndrome and T2DM.22, 23, 28 Drugs that interfere with the catabolism NPs and extent their half‐lives, such as the sacubitril/valsartan could be very useful for the treatment of obesity‐related hypertension.29

2.5. The renal compression factor

Increased visceral and retroperitoneal fat may increase the BP by physical compression of the kidneys as has been demonstrated by several studies.30, 31 Obese patients with increased visceral fat have increased intra‐abdominal pressure compressing the renal veins, lymph vessels, ureters, and renal parenchyma and causing elevations of BP as high as 35‐40 mm Hg.32 In addition, it has been shown in both animals and men that chronic accumulation of retroperitoneal fat could encapsulate the kidneys, adhere tightly to renal capsule, and invade the renal sinuses, causing additional compression and further increasing the intrarenal pressures.33, 34, 35 In support of this concept, are the findings from experimental studies in obese dogs where there was elevation in the renal interstitial hydrostatic pressure by 19 mm Hg compared to 9‐10 mm Hg in lean dogs.36 The increase in the intra‐abdominal fat will eventually compress the thin loops of Henle and vasa recta and reduce the renal tubular and medullary blood flow leading to increase in the renal fractional sodium reabsorption and increase in BP.36 Measures to decrease the intra‐abdominal and retroperitoneal fat have been associated with improvement of BP and the metabolic adverse effects of obesity. These beneficial effects were demonstrated in a pilot study of intra‐abdominal fat reduction with bariatric surgery and omentectomy.37

3. DISCUSSION

The data presented in this review demonstrate that the obesity‐related hypertension is a multifactorial condition and consists of an interplay of several factors including leptin, the SNS, the RAAS, the NPs, and the renal compression.4, 5, 6, 7 All these factors, their individual mechanism of action and their interplay are listed in Table 1 and depicted in Figure 1. Therefore, understanding their role in the development of obesity‐related hypertension is crucial in designing therapeutic options. The most important therapeutic factor is lifestyle changes with diet and exercise, including bariatric surgery in the morbidly obese. Weight loss has been shown to increase the plasma levels of adiponectin, an adipokine released from the adipocytes, which has vasodilating properties and increases the levels of leptin and also promotes weight loss through suppression of appetite and early satiety.28 Adiponectin levels have been shown to increase with the use of the PPARγ agonists thiazolidinediones (TZDs), drugs that can be used for the treatment of obese T2DM.28 Weight loss will also decrease the SNA, increase the NP levels, and decrease the renal compression, all actions associated with decrease in BP.6 Other means that can be used effectively for the treatment of obesity‐related hypertension are drugs that antagonize the RAAS and at the same time prevent the degradation of NPs. Such a drug is the neprilysin inhibitor sacubitril/valsartan. Its action is associated with increased peripheral vasodilation, decrease in systemic vascular resistance, and increase in diuresis and natriuresis with plasma volume contraction and decrease in BP.29 Of course, the use of diuretics is very important as well, but their use should be tempered in obese diabetic subjects. However, diuretics can be used together with ACE inhibitors and ARBs that provide protective effects against worsening of diabetes. In addition, the use of aldosterone antagonists has been shown to be useful in the treatment of obesity‐related hypertension and protect against target organ damage.38 Another class of drugs that can be used successfully in obese diabetic hypertensive patients are the recently released by the FDA sodium‐glucose cotransporter‐2 (SGLT2) inhibitors.39 These drugs promote renal salt and water excretion through osmotic diuresis from glucose excretion with loss of calories and weight. These drugs have been shown to have besides antihypertensive effects, also protective effects against CVD and HF. Some of these drugs can be used either alone or combination with other drugs that have synergistic effects. Among all these drug options, the first option for the treatment of obesity‐related hypertension is the sacubitril/valsartan either alone or in combination with a diuretic.

CONFLICT OF INTEREST

The author declares no conflict of interest.

Chrysant SG. Pathophysiology and treatment of obesity‐related hypertension. J Clin Hypertens. 2019;21:555–559. 10.1111/jch.13518