Hypertension and Obesity: Clinical Implications and Management
Prof. Dr. Marius Miglinas
Vilnius University, VUL Santariškių Klinikos Nephrology Center
Epidemiological studies show that the current global obesity epidemic began approximately 40 years ago. This epidemic is most commonly associated with two factors: decreased physical activity and overeating. A sedentary lifestyle is becoming increasingly prevalent, while less attention is being paid to physical activity in schools. Food industry marketing, technology, and the easy availability of inexpensive, high-calorie fast food are undoubtedly among the causes of the obesity epidemic. Interestingly, there is increasing evidence that other factors also contribute to obesity. These include lack of sleep, endocrine disorders, the effects of various factors on the fetus during the intrauterine period, and transgenerational transmission.
Worldwide, one billion people are overweight or obese [1]. There is a very close relationship between obesity and arterial hypertension (AH): up to 60% of obese individuals have AH [1]. A 5% increase in body mass raises the risk of developing AH by 20–30%. The combination of obesity and AH has important health consequences, increasing morbidity and mortality from cardiovascular diseases such as ischemic heart disease, heart failure, sudden death, chronic kidney disease, and stroke. On the other hand, obesity greatly increases the risk of treatment-resistant AH. Treating this type of hypertension requires multiple medications or even special procedures.
Not All Obese Individuals Have Arterial Hypertension
Although there is abundant and clear evidence of an association between obesity and AH, not every obese person has AH. The location of fat accumulation is very important. Therefore, although there is a clear relationship between obesity and arterial hypertension, not all obese individuals have elevated blood pressure. This depends on the distribution of adipose tissue.
When there is a constant energy surplus due to excessive calorie intake, subcutaneous tissue can no longer accommodate the excess, and fat begins to accumulate in ectopic sites: the abdominal cavity, around the heart, and around the kidneys. Therefore, fat accumulation in the abdominal cavity, retroperitoneal space, and tissues surrounding blood vessels is most closely associated with AH in obese individuals. Adipose tissue accumulation in these areas is characterized by phenotypic changes and adipocyte dysfunction: adipocytes secrete inflammatory molecules such as tumor necrosis factor-α, interleukin-6, interleukin-1, and monocyte chemoattractant protein-1. These abnormalities promote insulin resistance, hyperlipidemia, and atherogenesis and disrupt the secretion of adipokines and neuropeptides in adipose tissue [2].
Negative Metabolic Changes
Adipocytes produce and release adipokines such as leptin, resistin, adiponectin, and visfatin. Adiponectin, ghrelin, and endocannabinoids are associated with the development of insulin resistance. Leptin is a peptide hormone that acts on the hypothalamus in healthy individuals, reducing appetite and stimulating sympathetic nervous system activity. In obese individuals, resistance to the appetite-reducing effects of leptin develops, while its stimulatory effect on the sympathetic nervous system remains.
This selective leptin resistance has been explained in various ways. It is believed that obesity-related metabolic changes negatively affect the brain. Recent radiological studies have demonstrated reductions in the volumes of the hippocampus and prefrontal cortex in obese individuals. These changes in brain structures are caused by a deficiency of brain-derived neurotrophic factor. This factor plays a crucial role in neuronal survival, synaptic plasticity, learning, and memory and regulates energy and metabolic processes.
A sedentary lifestyle and high consumption of calorie-dense foods can reduce levels of brain-derived neurotrophic factor. Meanwhile, physical activity and intermittent fasting promote the production of this factor and its signaling in many areas of the brain.
The Cost of Obesity – Arterial Hypertension
Thus, obesity promotes activation of the sympathetic nervous system as a compensatory mechanism to increase resting energy expenditure and restore energy balance. However, the price paid for this metabolic effect is the development of hypertension [3]. The increased activity of the sympathetic nervous system is not generalized. It increases selectively in organs that are important for blood pressure regulation—the kidneys, heart, and blood vessels of skeletal muscles. In the kidneys, this leads to increased renin secretion and sodium reabsorption [4].
Sympathetic nervous system activity in the brain can also increase independently of leptin. Proopiomelanocortin neurons are present in various brain structures. Stimulation of melanocortin receptors in these neurons also increases blood pressure. Most of these receptors are found in the hypothalamus, amygdala, and paraventricular nuclei. There is evidence that a high-calorie diet and increased body mass stimulate proopiomelanocortin neurons. The proopiomelanocortin system in the brain not only regulates energy balance but also contributes significantly to activation of the sympathetic nervous system and the development of hypertension. These new findings raise hopes for the discovery of new and effective treatments for obesity and its related complications in the near future.
The Danger Posed by Abdominal Fat
There is ongoing debate about the volume of abdominal fat that dangerously disrupts the body's homeostasis and causes diseases such as ischemic heart disease, hypertension, heart failure, type 2 diabetes, metabolic syndrome, obstructive sleep apnea, colorectal, esophageal, breast, and prostate cancer, prostate hyperplasia, and chronic kidney disease, as well as increasing the risk of thrombus formation in arteries and veins and decreasing muscle mass (sarcopenia).
There are data suggesting that the volume of abdominal fat considered dangerous to health is approximately 250 cm³. The amount of intra-abdominal fat can be assessed using various methods, including computed tomography and magnetic resonance imaging. However, these techniques are expensive or involve radiation risks. Dual-energy X-ray absorptiometry (DEXA) is very useful for assessing the amount of abdominal fat. The examination is relatively inexpensive and brief, and the patient is exposed to very low levels of radiation.
Ectopic adipose tissue can accumulate in the retroperitoneal space and penetrate the renal sinuses, causing compression of the renal parenchyma and increased intrarenal pressure. This leads to compression of the loops of Henle and increased sodium reabsorption in the renal tubules. As a result, hypervolemia develops in obese individuals, leading to hypertension.
Importance of Increased RAAS Activity
The increased expression of components of the renin-angiotensin-aldosterone system (RAAS) in adipose tissue and the increased secretion of the angiotensin gene in adipocytes indicate that increased RAAS activity is very important in obesity and hypertension. Stimulation of angiotensin receptors disrupts lipolysis and promotes lipogenesis. Thus, the renin-angiotensin system is important not only for increasing blood pressure but also for regulating adipose tissue mass.
Increased production of angiotensin II in perivascular adipose tissue has a particularly negative effect on vascular function [5, 6]. Increased circulating aldosterone levels may also be associated with the development of hypertension in obese individuals. Ectopic adipose tissue produces a factor that stimulates mineralocorticoids. Therefore, obese individuals often have increased aldosterone concentrations. This also causes hypervolemia and the development of AH.
Mineralocorticoid receptors in the renal tubules can also be stimulated through an aldosterone-independent pathway. There is increasing evidence that adipose tissue produces Rac1 (guanosine triphosphatase), which activates mineralocorticoid receptors independently of aldosterone. Due to these changes, blocking mineralocorticoid receptors is highly effective in treating AH in obese patients.
The Impact of Changes in Intestinal Bacteria on Obesity
Recent data suggest that changes in intestinal bacteria may be associated with metabolic disorders that can lead to obesity and AH. A high-fat diet has a particularly negative effect on the intestinal microflora and causes changes in its composition. Bacterial lipopolysaccharides regulate the secretion of hormones such as insulin in adipose tissue and can cause changes in glucose homeostasis and chronic inflammatory reactions.
Lifestyle Changes and Medications – Important Components of AH Prevention
Lifestyle changes are a key component of obesity reduction programs. Lifestyle modification is also very important and is recommended for the prevention and treatment of AH. A meta-analysis of more than 25 randomized controlled trials showed that for each kilogram of body mass reduction, AH decreased by 1.05/0.92 mm Hg [7].
Unfortunately, weight-reducing drugs are not mentioned in current AH treatment guidelines, but they can be very beneficial in reducing AH in obese individuals. Drugs that reduce body weight, such as orlistat, lorcaserin, the combination of phentermine and topiramate, and liraglutide, can successfully reduce both patients' body weight and AH [7]. Reducing body weight through bariatric surgery also significantly reduces both arterial blood pressure (ABP) and mortality from cardiovascular diseases, as well as the incidence of stroke [7].
Apparently, there are no specific recommendations for any class of drugs for obese patients with AH in arterial hypertension treatment guidelines, possibly because of a lack of evidence. Considering the neurohumoral mechanisms and increased volemia associated with obesity, renin-angiotensin system inhibitors and diuretics are suitable first-line drugs. Undoubtedly, most patients with AH require two or more drugs to treat AH.
Various clinical trials that included a significant proportion of obese patients established the effectiveness of dihydropyridine calcium channel blockers in reducing ABP and preventing related complications. It should be noted that obese patients have a higher risk of developing peripheral edema when prescribed dihydropyridine calcium channel blockers. From a pathogenetic perspective, aldosterone receptor antagonists, mineralocorticoid receptor antagonists, and centrally acting sympatholytics are also suitable for treating obese individuals with AH [7].
Source: Lietuvos gydytojo žinios
