Adipokines: Novel Players in Resistant Hypertension

Abstract

Resistant hypertension (RH) is a multifactorial disease, frequently associated with obesity and characterized by blood pressure above goal (140/90 mm Hg) despite the concurrent use of ≥3 antihypertensive drugs of different classes. The mechanisms of obesity‐related hypertension include, among others, aldosterone excess and inflammatory adipokines, which have demonstrated a significant role in the pathogenesis of metabolic syndrome and RH. This review aims to summarize recent studies on the role of the adipokines leptin, resistin, and adiponectin in the pathophysiology of RH and target‐organ damage associated with this condition. The deregulation of adipokine levels has been associated with clinical characteristics frequently recognized in RH such as diabetes, hyperactivity of sympathetic and renin‐angiotensin‐aldosterone systems, and vascular and renal damage. Strategies to regulate adipokines may be promising for the management of RH and some clinical implications must be considered when managing controlled and uncontrolled patients with RH.

Resistant hypertension (RH) is a condition in which blood pressure (BP) remains above goal (140/90 mm Hg) despite the concurrent use of ≥3 antihypertensive drugs of different classes (uncontrolled RH [UCRH]). Ideally, one of these agents should be a diuretic, and all agents should be prescribed at optimal doses. Also, the definition includes a subgroup of patients with RH whose BP is controlled using ≥4 antihypertensive medications (controlled RH [CRH]).1

RH is considered an extreme phenotype and some studies have demonstrated that RH, diabetes, obesity, metabolic syndrome, and sleep disorders share common mechanisms.1 These pathophysiologic mechanisms include hyperactivity of renin‐angiotensin‐aldosterone system (RAAS) and sympathetic system, endothelial dysfunction,2 early damage in target organs including arterial stiffness,3 left ventricular hypertrophy (LVH),4 microalbuminuria,5 and deregulation of inflammatory adipokines.6

A close relationship between obesity and RH has been recognized, although the mechanisms are not fully elucidated. It includes (1) impaired sodium excretion, (2) increased sympathetic nervous system (SNS) activity, and (3) activation of the RAAS.7

The precise causes of impaired natriuresis are still unknown because there are several compensatory mechanisms and abnormalities that cause hypertension (HTN). Recent studies have suggested that overweight/obesity may accompany natriuresis impairment and BP increases in hypertensive patients.8, 9 First, this condition is caused by increased renal sodium reabsorption. However, in patients with prolonged obesity, a severe and complex scenario with neurohumoral activation and increased BP levels, renal vasodilation, and glomerular hyperfiltration results in a progressive loss of kidney function.8, 9 In turn, increased renal sympathetic and RAAS activities and altered intrarenal physical forces have been suggested as potential mechanisms that mediate obesity and increased renal sodium reabsorption.7

The SNS activation in obesity has been associated with insulin resistance, thus suggesting that hyperinsulinemia can trigger sympathetic nerve activity.10 It has been reported that a chronic increase in sympathetic outflow decreases β‐adrenergic responsiveness by a downregulation of β‐adrenergic receptors, which are known to mediate energy expenditure either at rest or after food intake.11 Furthermore, leptin—an adipokine produced in adipose tissue—may increase SNS outflow by binding to its receptors in the hypothalamus,12 a regulatory center of satiety and autonomic nervous system, causing obesity and autonomic dysfunction. Moreover, studies have indicated a bidirectional relationship between SNS and RAAS: renal sympathetic nerves stimulate renin release while angiotensin activates adrenergic function, which indicates an important interaction to understand the control of renal function.13

Obesity is accompanied by elevated plasma aldosterone levels.14 This association may occur because soluble factors derived from adipose tissue stimulate adrenal aldosterone secretion.15 Increased levels of systemic RAAS markers (circulating angiotensinogen, renin, and aldosterone levels) have been demonstrated in obese compared with lean patients.16 In this same study, weight loss was associated with reduction of systolic ambulatory BP measurement and of RAAS components. The mechanisms that explain the decrease of aldosterone levels in weight loss are less clear. It is suggested that renin activity reduction may contribute to the decrease, as well as the possible reduction of adipocyte products and oxidized fatty acid derivatives.16 Moreover, it has been suggested that HTN in lean patients is mediated by an increase in peripheral vascular resistance, whereas in individuals with obesity, it is mediated, in part, by increased intravascular volume, cardiac output,17 and proximal tubule sodium absorption in the kidney.18 Crosstalk signaling between components of the RAAS, such as angiotensin II and aldosterone, can also regulate vasoconstriction independently of renal control.19, 20 Although some studies have demonstrated that aldosterone levels, inflammatory adipokines, and insulin resistance are increased in HTN apart from the presence of obesity,21, 22 it seems evident that obesity has a role in exacerbating those unfavorable alterations.

Finally, aldosterone excess may be relevant in mediating the lack of BP control and maladaptive changes in the renal, cardiovascular, and central nervous systems.23 The detection of aldosterone excess in RH24 is clinically important once it indicates increased levels of aldosterone without diagnosis of primary hyperaldosteronism (exclusion criteria includes the cutoff value of aldosterone‐plasma renin activity ratio [ARR]>20 ng/dL per ng/mL/h). Indeed, aldosterone scape/breakthrough is a well‐known phenomenon associated with unfavorable prognosis25 that follows the patient in treatment with renin‐angiotensin system blockers, which are widely used for treating RH. In this way, mineralocorticoid receptor (MR) blockade, besides the current use in the treatment of RH,26 emerges as a therapeutic strategy to downregulate proinflammatory adipokines, such as leptin27 and resistin,28 and to increase the expression of adiponectin.29 This context highlights the idea that deregulation of adipokines might be closely linked to cardiovascular and renal adverse outcomes involved in RH disease.

General Aspects of Adipokines

Overweight and obesity have been considered a growing public health problem because of their associated cardiovascular morbidity and mortality and also because of their associated disorders including insulin resistance, diabetes, atherosclerosis, HTN, and chronic kidney disease.30 Indeed, adipose tissue has been an emergent target of studies because of its wide range of biological properties, especially the production of adipokines.31

Leptin was the first discovered adipokine, ascribing an endocrine function for the adipose tissue.32 The main action of leptin occurs mainly on hypothalamic targets, regulating appetite and increasing energy expenditure through sympathetic stimulation.33 However, clinical trials have demonstrated that the majority of obese patients have increased levels of leptin accompanied by selective leptin resistance34 status that explains, at least partially, obesity‐associated HTN. This novel concept has emerged showing that the resistance appears to be primarily limited to the metabolic (satiety and weight‐reducing) actions of systemic leptin, but not to the renal sympathetic activation effects.35 Hence, this condition has been characterized by increased SNS activity probably as a result of leptin sympathoexcitatory effect,34 with one potential mechanism involving downstream signaling pathways in the hypothalamus.36 In the kidney, sympatoactivation, besides decreased natriuresis leading to volume retention, leptin may contribute to increased BP levels.34 Moreover, leptin has additional detrimental effects in cardiovascular system such as promoting atherosclerosis by stimulation of monocyte migration,37 inflammation and thrombosis processes, hypertrophy of cardiomyocytes, and myocardial extracellular matrix remodeling.38

Another adipokine—resistin—is a protein predominantly synthesized by macrophages but is also in the adipose tissue and is increased in inflammatory conditions.39 Some studies demonstrated that levels of this adipokine are increased in obesity, insulin resistance, and hypertension.28, 40 However, these findings are conflicting41 and the lack of studies has provided some challenge to achieve clear conclusions. Studies have associated resistin concentrations and RAAS activity. Patients with primary hyperaldosteronism demonstrated higher resistin levels, which was associated with body mass index (BMI), leptin level, and cardiac morphological changes, independently of the presence of metabolic syndrome, suggesting a possible aldosterone‐mediated resistin role in patients with cardiovascular risk.42 On the other hand, patients with HTN who underwent a low‐sodium diet demonstrated higher resistin levels and RAAS activity compared with those with high dietary sodium intake. However, resistin concentrations were not associated with plasma renin activity or serum aldosterone on either diet, which suggested that either dietary regimen (low or high sodium) could affect resistin independently of circulating RAAS components, or the RAAS variability in the dietary intervention was too small to observe an association with resistin.43 Moreover, resistin showed proinflammatory properties by increasing secretion of cell adhesion molecules and other cytokines such as tumor necrosis factor α and interleukin 6.44 In addition, a study revealed that resistin increased the proliferation of vascular smooth muscle and endothelial cells.45 Although resistin is better grounded in experimental models, it is possible that this adipokine participates in the pathophysiology of cardiovascular effects in humans via macrophages involving inflammatory process related to obesity.

Adiponectin is the most abundant adipokine produced by the adipocytes. It exists at the range of 3 μg/mL to 30 μg/mL in plasma and, unlike all of the aforementioned adipokines, has been suggested to improve insulin sensitivity and prevent atherosclerosis and inflammatory processes.46 This adipokine was inversely associated with BMI and a reciprocal counter‐regulatory mechanism with proinflammatory cytokines in adipose cells has been demonstrated by previous studies.47, 48 Low plasma levels of adiponectin were considered a predictor of cardiovascular outcomes in the general population and among patients with diabetes.49 Moreover, it was associated with endothelial dysfunction,50 LVH progression,51 and arterial stiffness.52 Previous studies have revealed that hypoadiponectinemia is an independent risk factor for HTN53 and also predicts the development of HTN in normotensive patients after adjustment for confounding factors.54 Finally, the RAAS components have been associated with adiponectin regulation, and the direct effect of aldosterone on adipose tissue has been investigated. An experimental study has identified that aldosterone inhibits adiponectin expression and protein production in 3T3‐L1 adipocytes, suggesting that adiponectin may mediate aldosterone action in insulin resistance and cardiovascular events.55 Some studies have demonstrated that RAAS‐acting drugs can increase adiponectin levels in hypertensive patients56, 57 with accompanying improvement in insulin sensitivity.58 Moreover, patients with hyperaldosteronism have lower levels of adiponectin compared with hypertensive patients.59 Thus, pharmacologic strategies to increase adiponectin levels may be beneficial in preventing cardiovascular damage and metabolic disorders in HTN.

Preliminary Clinical Findings in RH

Prospective clinical studies have indicated that obesity is a strong predictor of lack of BP control.60 Hence, obesity is considered a common characteristic of RH.1 In this context, we have recently investigated that adipokines deregulation might represent a potential contributor to antihypertensive treatment resistance (Figure).

Figure 1.

Potential comorbidities linked to adipokine deregulation in resistant hypertension.

We demonstrated that plasma adiponectin levels are associated with a pattern of autonomic activity in RH populations with type 2 diabetes (T2D) and without type 2 diabetes (non‐T2D).61 These findings suggest a relationship between diabetes, obesity, and autonomic imbalance (characterized by a hyperactive sympathetic system and a hypoactive parasympathetic system) in RH patients. Increased heart rate variability, used to assess autonomic imbalance, was positively correlated with adiponectin in all patients (T2D and non‐T2D), but it was noteworthy that autonomic imbalance may contribute to a greater impact on the onset of diabetes and obesity when compared with non‐T2D RH patients.61 Moreover, we have found a significant association between sympathetic activity and aldosterone levels but not with leptin.62 Increased aldosterone may modulate both sympathetic overactivity and disturbances of glucose metabolism by (1) classic effects of salt retention and volume expansion and (2) non‐classic mechanisms through inflammation and oxidative stress pathways.23 Recently, it has been considered the existence of crosstalk between aldosterone's genomic and nongenomic pathways which allowed unifying the regulation of electrolyte and volume homeostasis in addition to affect extrarenal properties such as inflammation.63, 64 As a limitation of our study, a small sample size might explain the negative findings of leptin levels and sympathetic activity association in RH patients.62

Increasing evidence has demonstrated that some important clinical characteristics differ between CRH and UCRH patients.65 Recent studies tested the hypothesis that higher leptin and resistin and lower adiponectin levels could participate as complicating factors in the lack of BP control in RH.66, 67, 68 It was revealed that patients with UCRH had higher leptin levels when compared with those with CRH and patients with well‐controlled HTN. In addition, the UCRH subgroup had higher aldosterone levels and heart rate than the CRH and HTN groups. Plasma leptin was associated with systolic BP, diastolic BP, and aldosterone levels only in patients with UCRH.66 These findings showed that leptin might mediate hyperactivity of the sympathetic system and RAAS in RH. Moreover, leptin may contribute to metabolic disturbances such as insulin resistance and endothelial dysfunction as a result of inflammation and oxidative stress that accelerate RH development.23 Even with these suggested mechanisms, it remained unclear whether aldosterone and leptin are directly or indirectly interconnected in RH disease.

We also demonstrated that hypoadiponectinemia and aldosterone excess may be implicated in the resistance to antihypertensive therapy as a result of their association with greater arterial stiffness. Adiponectin was positively correlated with systolic BP and pulse pressure, both in office and ambulatory BP monitoring measurements, and aldosterone concentration. Moreover, adiponectin was a predictor of arterial stiffness, measured by pulse wave velocity, in patients with UCRH, but no association was found between this adipokine and endothelial function or cardiac hypertrophy.67 Again, even though it was a cross‐sectional study and causal inferences cannot be made, these findings support a potential link between hypoadiponectinemia and vascular damage in RH.

Finally, our study evaluated the association of leptin, adiponectin, and resistin with markers of target organ damage such as arterial stiffness, left ventricular hypertrophy, and microalbuminuria. Although resistin was higher in the UCRH subgroup, it was not associated with target organ damage in both subgroups. On the other hand, leptin and adiponectin were predictors of arterial stiffness, adjusted for BMI, age, and sex in UCRH patients. In addition, adiponectin levels predict microalbuminuria—a marker of early renal damage—after the adjustment for BMI, age, and sex in this same subgroup.68

Taken together, these clinical evidences suggest that patients with UCRH are exposed to a higher cardiovascular risk because of vascular and renal damage.

Implications and Therapeutic Strategies

The management of RH is challenging and requires nonpharmacologic and pharmacologic strategies. Indeed, regulation of adipokines might be a potential strategy involving RH treatment. Weight loss should be encouraged to revert metabolic disorders and to favor BP control.69 Reduction in body weight has been associated with beneficial effects by reducing RAAS components, which may contribute to BP reduction.16 Moreover, a reduction in dietary salt intake must be part of RH treatment.70 A randomized crossover trial showed an extreme salt sensibility by patients with RH, who manifested a reduction in office and 24‐hour ambulatory BP in response to a low‐salt diet.70 An experimental study has demonstrated that a long‐term, low‐sodium diet increases the expression of adiponectin and reduces both proinflammatory cytokines and insulin levels in obese diabetic mice.71 It has been suggested that high dietary salt intake does not suppress angiotensin II stimulation of renin and aldosterone release, resulting in an inappropriate increase in sodium and fluid retention in hypertensive patients,72 which supports an intense approach toward patients following a hyposodic diet (in fact, a huge challenge in clinical practice).

The RAAS‐acting drugs have been widely used in RH therapy. In addition, MR antagonists have been considered of potential benefit when added to a multidrug regimen in the treatment of RH.26 In this context, pharmacologic strategies to regulate adipokines levels seem to be of great clinical interest since they may implicate benefits on preventing cardiovascular and metabolic disorders. Drugs that interfere with RAAS (angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers) have been reported to improve the adipokine profile in hypertensive individuals.57, 58, 73 Moreover, MR blockade improves expression of adiponectin and reduces expression of proinflammatory factors, reversing obesity‐related changes.29 Thus, the management of therapeutics may benefit RH patients by protective mechanisms caused by the adequate regulation of adipokines levels.

Beyond conditions of aldosterone excess and obesity, hyperleptinemia and leptin resistance linked to sympathetic system hyperactivity might indicate the leptin receptor as a potential target for future interventional studies.73

Finally, it can be expected that management of HTN in this subset of patients includes optimization of therapy in RH‐related disorders, such as diabetes74 and dyslipidemia,75 to reduce cardiovascular risk.76

Conclusions

All of the above‐mentioned findings suggest that strategies to regulate adipokines may be promising for the management of patients with RH (both CRH and UCRH). This latter subgroup is probably exposed to increased cardiovascular risk and may reflect a worse prognosis, although this hypothesis should be tested using prospective studies.

J Clin Hypertens (Greenwich). 2014;16:754–759. DOI: 10.1111/jch.12399. © 2014 Wiley Periodicals, Inc.