Obesity and resistant hypertension: Never ending story

1. INTRODUCTION

The global epidemic of obesity is becoming one of the major public health problems in the modern era. Systemic review that included 68.5 million individuals in order to evaluate the trend in the prevalence of overweight and obesity among children and adults between 1980 and 2015 showed that the prevalence of obesity in both children and adults has doubled in 73 countries.1 It seems that the largest problem is the significant increase in obesity prevalence in children and developing countries. The serious consequence of the epidemic of obesity is the burden of illness related with excess body weight. Namely, obesity was related with 7.1% of deaths from any cause and 4.9% of disability worldwide.1 Elevated body mass index (BMI) represents an independent risk factor for the development of hypertension, type 2 diabetes mellitus, dyslipidemia, ischemic heart disease, stroke, chronic kidney disease, non‐alcoholic fatty liver disease, some malignancies, and obstructive sleep apnea.2, 3, 4, 5 In the United States, almost half of hypertensive patients are obese.6 Moreover, 35% of the US obese subjects have hypertension, in comparison to 18% of normal‐weight individuals with concomitant arterial hypertension.7

According to the guidelines, the definition of resistant hypertension is based on the lack of normalization of blood pressure (BP) during the treatment with three antihypertensive drugs in maximal doses, including one diuretic.8, 9 However, there is a significant difference in definition of normal BP values according to European 8 and American guidelines.9 The European guidelines claimed that normal BP is <140/90 mm Hg,8 whereas this cut‐off value in the American guidelines is <130/80 mm Hg. This is main reason why the percentage of resistant hypertension is higher in the studies that used the American guidelines.10 There are several common causes of resistant hypertension: secondary hypertension, patient's non‐adherence to antihypertensive treatment, white coat hypertension, and fluid retention. The last cause of resistant hypertension was the reason why European guidelines emphasized the importance of a long‐acting thiazide‐like diuretic, a chlorthalidone or an indapamide, and a mineralocorticoid receptor blocker, usually spironolactone, in attempt to achieve BP control.8

In this issue of the Journal, Haddadin et al11 investigated the prevalence of resistant hypertension in population of overweight and obese patients. Using 2017 ACC/AHA Guidelines and threshold ≥130/80 mm Hg for arterial hypertension, the authors reported that apparent treatment‐resistant hypertension was found in 13.6% overweight and obese patients, which represented 15.4% of subjects treated with antihypertensive medications.11 True resistant hypertension confirmed with out‐of‐office elevated BP was found in 6.7% of the study population and 7.4% among patients treated with antihypertensive medications.11 Out‐of‐office BP measurement was based on intermittent home BP measurement rather than the more accurate 24‐hour ambulatory BP measurement (ABPM) due to the limited resources. The authors correctly stated section that could be important limitation of their study because intermittent home BP measurement may be less accurate than 24‐hour ABPM also in relation to the fact that patients are not always properly trained to measure BP correctly. Home BP measurement decreased the percentage of refractory hypertension for more than 50% in comparison with clinic measurement. The authors reported three main reasons for pseudo‐resistant hypertension: medications non‐adherence (14%), suboptimal medical regimen (11%), and white coat hypertension (12%). Possibly the large percentage of pseudo‐resistant hypertension might be partly ascribed to scarce quality of home BP measurement. The percentage of true refractory hypertension in the whole population of hypertensive overweight and obese patients was only 0.9%,11 which is in line with previous large study that included 30 239 hypertensive patients that found true refractory hypertension in 0.5% patients.12 However, in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study the cutoff BP value for diagnosis of resistant hypertension was ≥140/80 mm Hg12 and ≥130/80 mm Hg in the current study.11 Therefore, one would expect that the prevalence of resistant hypertension in the current study would be significantly higher. These data suggest that true antihypertensive treatment failure is rare, even though resistant hypertension is relatively common among treated patients with hypertension (18%‐40%).

The authors showed that prevalence of resistant hypertension gradually increased with BMI, from overweight patients, across class I and II obesity, to class II obesity patients.11 However, BP values, prevalence of coronary artery disease and heart failure with preserved ejection fraction also increased in the same direction, with increase in BMI.

The multivariate regression analysis revealed that black race, BMI, diabetes mellitus, heart failure with preserved ejection fraction, and chronic renal failure stage ≥3 were independently associated with true resistant hypertension.11 In the REGARDS study was found that blacks, albuminuria, and diabetes were independently associated with resistant hypertension.12 The same study demonstrated that the median 10‐year Framingham risk for coronary heart disease and stroke was higher among participants with refractory hypertension.12

Many pathophysiological mechanisms may be involved in the development of hypertension in obesity: insulin resistance, inflammation, the renin‐angiotensin‐aldosterone system, oxidative stress, the sympathetic nervous system and adipokines (such as adiponectin and leptin).

Insulin resistance and oxidative stress are typically seen in patients with increased visceral adiposity, which is related with increased sympathetic nervous system activity.13 Obstructive sleep apnea, which is very often seen in obese subjects, also induces sympathetic stimulation and further increases BP in obese population.14 Grassi et al recently reported that sympathetic nervous activity gradually increased from normoweight patients across overweight subjects to obese individuals, independently of sleep apnea syndrome.15 Interestingly, sympathetic nervous activity directly correlated with BMI and waist‐to‐hip ratio, clinic BP, total cholesterol, low‐density lipoprotein cholesterol, and triglycerides, but did not correlate with plasma insulin, glucose, and homeostatic model assessment for insulin resistance.

Increased adipose tissue is related with increased angiotensin type 1 and 2 receptor expression as well as elevated circulating angiotensin II, angiotensin‐converting enzyme, and aldosterone levels, which is related with elevated BP.16 Increased circulating adipokines could induce increased activity of the renin‐angiotensin‐aldosterone system.17 The elevated renin‐angiotensin‐aldosterone system activity alters the renal hemodynamics by causing afferent renal arteriolar dilation and efferent renal arteriolar vasoconstriction.17 The increased activity of sympathetic nervous system and renin‐angiotensin‐aldosterone system in obesity induces impairment in natriuresis, increased renal sodium retention, and consequently extracellular volume expansion, which provokes hypertension in obesity.13

Recently, a published study revealed that subclinical inflammation defined by increased levels of tumor necrosis factor‐alpha (TNF‐alpha), interleukins (IL‐6, IL‐8, IL‐10), leptin, and adiponectin were related with resistant hypertension in obese patients.18

The role of obesity on hypertension development was also confirmed in the studies that showed significant reduction in BP after weight reduction.19 There are different methods of weight reduction: lifestyle changes, pharmacological intervention, and bariatric surgery.19, 20, 21 Lifestyle changes such as diet and exercise usually cannot result with clinically significant weight loss.19, 20 Pharmacological intervention has not provided satisfactory results so far. Bariatric surgery is an invasive method, but it provides more constant BMI reduction with greater probability of long‐term BP decrease.21 Even though data regarding long‐term outcomes are lacking, bariatric surgery seems to provide an important renal, cardiovascular, and mortality benefit in obese patients than other types of weight loss.21

Haddadin et al conducted a cross‐sectional study, and therefore, potential mechanisms responsible for development of resistant hypertension in overweight and obese patients cannot be inferred. However, it seems that besides increased BMI, black race, diabetes, heart failure with preserved ejection fraction, and chronic kidney disease were independently associated with true refractory hypertension in overweight and obese hypertensive patients.11

In our opinion, the current study showed several very important findings in overweight and obese hypertensive patients: (a) uncontrolled BP (≥130/80 mm Hg) was frequently seen in this population (26.1% in overweight and 48.2% in obese patients with BMI ≥ 40 kg/m²); (b) apparent treatment‐resistant hypertension ranged from 10.5% in overweight to 19.5% in patients with BMI ≥ 40 kg/m²; (c) true resistant hypertension was significantly less frequent (from 4.7% in overweight to 11.5% in severely obese patients); and (d) the prevalence of true resistant hypertension in the whole population of obese patients was very low (0.9%) and does not differ from non‐obese populations.11

In conclusion, we would like to emphasize that true resistant hypertension is not prevalent even in population with high‐risk cardiovascular profile. Pseudo‐resistant hypertension represents significantly larger problem, and we should be particularly cautious regarding medications non‐adherence, suboptimal regimen, and white coat effect. Improved medical approach that includes better communication with patients regarding their antihypertensive therapy, and more frequent use of 24‐hour ABPM would significantly reduce the prevalence of pseudo‐resistant hypertension and decrease the number of unnecessary antihypertensive medications that these patients should take every day.

CONFLICT OF INTEREST

None.