Introductory Chapter: Hypertension – A Perspective

1. Introduction

High blood pressure or hypertension (HTN) is characterized by persistent raised arterial pressure. According to international guidelines, hypertension has been defined by systolic blood pressure (SBP) equal to or more than 130 mmHg and/or diastolic blood pressure (DBP) of more than 80 mmHg [1]. The definition and categories of HTN are under constant review, and the present consensus is that persistent SBP/DBP readings of 140/90 mmHg should be treated to achieve a target of 130/80 or less.

The ACC/AHA hypertension treatment guidelines have categorized hypertension into different stages: (1) normal (<120 systolic and <80 mm Hg diastolic), (2) elevated (120–129 systolic and <80 mm Hg diastolic), and (3) stage 1 hypertension (130–139 systolic or 80–89 mm Hg diastolic) and stage 2 hypertension (≥140 systolic or ≥90 mm Hg diastolic). It has been suggested that these categories should be confirmed by at least two readings at two different time points, and an average of those readings should be taken. Further, the final classification should be based on the highest SBP/DBP category [2].

2. Epidemiology

HTN is one of the most common chronic diseases and is a major causative factor for cardiovascular, renal, and cerebrovascular diseases and their associated morbidity and mortality. According to a WHO report published in 2021, approximately 1.3 billion adults, between the age of 30 and 79 years suffer from hypertension, with two-third of them being from low- and middle-income countries. Nearly 50% of patients remain undiagnosed, and only one out of five patients have their blood pressure under control. A recent comprehensive report which analyzed global prevalence of hypertension in 184 countries covering 99% of the total world population showed that the incidence of hypertension has doubled in the last 30 years (1990–2019) in adults in the age range of 30–79 years. The prevalence was found to be lowest in Canada and Peru for both men and women, whereas it was lowest in men in some European countries such as Switzerland, Spain, and UK. Several low-income countries, which included Bangladesh, Ethiopia, Solomon, and Eritrea also showed lower incidence of hypertension. High-income countries and emerging high-income countries such as Taiwan, Turkey, South Africa, and Iran showed higher treatment and control of HTN as compared to low-income countries. The highest prevalence of HTN was seen in sub-Saharan Africa, Oceania, and South East Asia [3].

3. Etiology

Based on etiology, hypertension has been categorized into primary hypertension and secondary hypertension. When the primary cause of raised blood pressure cannot be determined, it is called primary or essential hypertension. In secondary hypertension, hypertension is secondary to medical cause such as renovascular hypertension and hypertension secondary to renal and adrenal disorders.

Primary hypertension is a multifactorial complex disease. The causative factors for primary hypertension are considered to be mostly unknown, but we do know several modifiable factors such as high salt intake (in salt-sensitive patients), high-fat diet, high alcohol intake, obesity, sedentary lifestyle, stress, insulin resistance, low potassium, and low calcium contribute to the pathogenesis of essential hypertension. Family history of hypertension is also a significant etiological factor in the pathogenesis of primary hypertension. Several gene loci have been identified which contribute to the pathophysiology and pathogenesis of hypertension. Studies in the last two decades have shown that there is a significant interaction between genetic factors and environmental/modifiable factors in the etiopathogenesis of primary hypertension.

4. Pathogenesis

Increased arterial pressure, which is a hallmark of hypertension, is the result of alterations in cardiac output and total peripheral vascular resistance. Dr. Page was the first one to propose that factors such as blood volume, vascular elasticity, caliber, reactivity, humoral factors, and neural stimulation influence blood pressure regulation. In recent years, additional mechanisms such as oxidative stress, inflammation, and microbiome have been identified to play an important role in HTN pathogenesis.

The kidney is the main effector as well as target organ of HTN. It produces renin, which cleaves angiotensinogen to form angiotensin I, which further is converted to angiotensin II (AngII) by the action of angiotensin-converting enzyme (ACE). This constitutes the renin-angiotensin system (RAS). Renin is produced as an inactive precursor prorenin in specialized juxtaglomerular cells of the kidney and is activated to renin on binding to prorenin receptor (PRR). Renin is secreted from JG cells on sensing reduced perfusion pressure, increased sympathetic activity, or increased availability of sodium chloride to macula densa cells [4].

Kidneys also regulate blood pressure by regulating pressure diuresis and natriuresis. First reported by Gyaton [5], increased blood pressure is now known to cause diuresis and natriuresis, resulting in normalizing the BP. It has been shown that acute rise in BP results in the translocation of sodium transporters, sodium hydrogen exchanger (NHE3), and the sodium-phosphate cotransporter isoform 2 from luminal cell membrane to apical microvilli of proximal tubules which hampers sodium reabsorption. However, chronically raised BP results in relocation of thiazide-sensitive sodium chloride cotransporter also to the apical microvilli and results in increased sodium reabsorption [6]. The kidneys also regulate blood pressure by modulating systemic sympathetic tone via renal afferent nerves. These nerves transmit sympathetic signals to the kidney and increase renin release and sodium reabsorption. Kidneys also are the site of immune activation and have been suggested to induce neoantigen formation in hypertension [6].

5. Role of vasculature

Vasculature perturbations in hypertension include increased AngII, catecholamines, and vasopressin production, and these responses are suggested to be mediated by G-protein signaling pathways. Decreased vasodilatation is an important feature of hypertension, and reduced NO signaling and endothelium-dependent vasodilatation mechanisms are said to contribute to decreased vasodilatation. Increased vascular remodeling involving smooth muscle cell hypertrophy and narrowing of arteriolar lumen also have been implicated in increased vascular resistance. Increased production of AngII, catecholamines, oxidative stress, and inflammation contribute to HTN-mediated vascular remodeling. Vascular remodeling is also known to promote arterial stiffening resulting in end-organ damage [7, 8].

6. Inflammation and immune mechanisms

There is ample evidence that there is increased production of pro-inflammatory cytokines, such as IL-17A, in the kidney and blood vessels in the hypertensive milieu. These cytokines promote fibrosis and modulate pressure natriuresis and sodium handling by kidney cells [9]. The immune activation has been shown to be mediated by increased oxidative stress in antigen-presenting cells and sympathetic outflow [10, 11].

7. Oxidative stress and hypertension

Reactive oxygen species (ROS) such as super oxide anions, hydroxyl radicals, hydrogen peroxide, and free oxygen radicals have been shown to play an important role in the pathophysiology of hypertension. There is an increased ROS production in various tissues such as kidney, heart, and vasculature in the hypertensive milieu. Increased activity of ROS-producing enzymes, NADPH oxidases, and NO synthases has been observed in hypertension [6]. Increased ROS production produces an imbalance between pro-oxidants and oxidants, resulting in oxidative stress in tissues and organs. Oxidative stress can induce vascular remodeling, induce sodium reabsorption in the kidneys, and activate pro-fibrotic metalloproteases [12]. High salt intake and increased AngII production have been shown to induce oxidative stress in vascular cells of kidneys. Both high salt intake and AngII have been found to increase NADPH oxidase levels and decrease SOD expression, leading to increased ROS generation and associated damage to renal cells. Recent studies suggest that mitochondria also have a role in ROS generation in HTN, through inhibiting SOD activity via Sirt3 (sirtuin3) [13].

8. Genetics and hypertension

Familial inheritance of hypertension is well established; however, no single gene has been found to be associated with primary hypertension. Several genes have been identified for highly inheritable monogenic syndromes associated with hypertension, which have helped to elucidate patho-mechanisms leading to high blood pressure. However, primary hypertension has been shown to be associated with the complex interaction of single-nucleotide polymorphisms (SNPs) in multiple genes. Through genome-wide association studies and through gene-specific genetic association studies, more than 1000 SNPs have been reported to be associated with hypertension [14]. These SNPs appear to interact with environmental factors as well as there are gene–gene interactions, resulting in hypertension. Recently, it has been shown that a genetic score based on multiple gene–gene interactions (polygenic risk score) may have a good predictive value [6].

9. Role of salt in hypertension

Dietary salt is an important modulator of blood pressure response in salt-sensitive hypertensives. Several epidemiological studies have confirmed the association of dietary salt with increased risk of HTN and the beneficial effects of salt reduction on reducing blood pressure [15]. In salt-sensitive hypertensives, there is impaired salt excretion by kidneys, and ingestion of high salt leads to increased peripheral vascular resistance due to endothelial dysfunction and increased vasoconstriction. Under low salt conditions, these subjects fail to increase peripheral vascular resistance [16].

The salt-mediated hypertension has been extensively investigated, and it is apparent that besides defective renal excretion, other mechanisms, such as intradermal accumulation and its subsequent effect on immune modulation such as macrophage stimulation, and vascular endothelial growth factor (VEGF) stimulation [17]. Besides this, high salt is known to T cells to generate IL-17A, which is known to promote vascular fibrosis and hypertrophy, endothelial dysfunction, and increased sodium retention in the kidneys. Increased sodium has also been reported to stimulate the secretion of pro-inflammatory cytokines, TGF-α, IL-6, and IL1-β [6].

10. Role of gut microbiome

In the past few years, the microbes harboring the gut have been extensively investigated for their role in several diseases, including hypertension. Under normal conditions, gut bacteria are said to be in symbiosis with its surroundings, meaning co-existing in harmony within gut. However, there is dysbiosis, i.e. imbalance between healthy and pathogenic bacteria in the gut in several diseases, including hypertension. It also shows a reduction in quantum and diversity of the gut microbiome under diseased conditions. Alterations in the gut microbiome has been observed in hypertensive and pre-hypertensive patients and in several models of hypertension, including spontaneously hypertensive rats and Dahl-sensitive rats [18, 19]. Microbes such as Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria have been found to be increased in hypertensive gut microbiome composition [20].

Emerging literature suggests that due to gut dysbiosis, there are changes in bacterial metabolites which influence blood pressure regulation [19]. Changes in gut microbial population in hypertension subjects and animal models have been shown to be influenced by a high salt diet, which causes increased levels of pro-inflammatory cytokine, IL-17A [21]. Dietary fiber-enriched foods such as vegetables and fruits and whole grains too have been shown to alter gut microbiome favorably in hypertensives. Dietary fibers are said to increase short-chain fatty acids, which are considered good anti-inflammatory products and also influence other pathways such as renin release by JG cells, vasculature, and autonomic nervous system [22]. Thus, dietary manipulations such as high-fiber diet, prebiotics, and probiotics appear to have therapeutic potential in decreasing the risk and treatment of hypertension.

11. Future perspectives

Despite increased detection and treatment of hypertension compared to the last decade, hypertension still is a significant public health problem responsible for cardiovascular diseases, renal failure, stroke, and retinopathy. This is probably due to several factors such as delayed diagnosis, lack of newer, more effective therapeutics, and accessibility to treatment. Thus, there is a need to develop public health awareness of hypertension, specifically in low-income countries, along with better and more accurate tools to detect hypertension. Further, there is a need to develop newer therapeutics based on recently discovered molecular mechanisms in the pathophysiology of hypertension. Dietary manipulations, lifestyle changes, and immunotherapy will play more role in preventive and therapeutic strategies for hypertension in the near future.