Analysis Of The Processes Involved In The Development And Progression Hypertension
Hypertension (HTN) is a major global health burden. It is the most prevalent chronic medical condition seen in primary care. 1 It is responsible for 10. 8% of all deaths in India. 2 It effects various organ like heart, kidney, brain, eyes, etc. HTN is directly responsible for 57% of all stroke deaths and 24% of all coronary heart disease deaths in India. It is a controllable disease. A 2mmHg population-wide decrease in BP can prevent 151,000 stroke and 153,000 coronary heart disease deaths in India. 3
HTN is divided into 2 groups: primary (or essential) and secondary hypertension. Essential hypertension has no clear etiology and accounts for 95% of cases. Secondary hypertension accounts for the remaining 5% of cases. 4 It has many clinical patterns and/or etiopathological forms which includes: essential HTN, secondary HTN, white-coat HTN, isolated systolic HTN, masked HTN, pulmonary HTN, pregnancy related HTN. 1 Clinical or office measurement of blood pressure (BP) is the classical diagnosis of HTN. It is defined as persistent elevation in office systolic BP >= 140 mmHg and or diastolic BP >=90 mmHg. This is equivalent to a 24 hr ambulatory BP monitoring average of >=130/80 mmHg or a home BP monitoring average >= 135/85 mmHg. 5
Regardless of the device used to assess BP, the conventional practice only provides us with values and patterns. A significant proportion of hypertensive patients are diagnosed at an advanced stage of the disease, because of the “silent” nature of the disease in most cases. 6 Thus identification of population at risk is a challenge and requires laboratory tests. Multiple biomarkers for HTN have been identified over the years and may shed light on the underlying processes involved in the development and progression of HTN.
Here, we discuss the important biomarkers of HTN to help better evaluate their utility and to better understand the pathophysiology, diagnosis, progression, and therapeutic efficacy of EH.
A Pubmed and google scholar search was performed, using “hypertension”, “biomarkers” and “markers” as search parameters, and also their relevant references were reviewed. A total of 150 articles were reviewed, among these only 64 articles were found relevant and were considered for this study.
Genetic and environmental factors contribute to development of HTN. Also a complex interactions of various hormones, local vascular factors, and neural mechanisms have a role to play. 7 The cause of secondary HTN includes primary hyperaldosteronism, Cushing's syndrome, etc. They have specific markers for diagnosis such as plasma metanephrine measurements, plasma aldosterone level, etc. 1 On the other hand, though essential hypertension accounts for 95% of all cases of HTN, its etiology is not clear. Different patients have different etiology for high blood pressure. 8 Endothelial dysfunction, oxidative stress, and inflammation play a major role in its development. 9-13 In this section we discuss various biomarkers of hypertension. Of the many available markers C-reactive protein, cytokines, uric acid, urine albumin excretion and nitric oxide gives us better understanding of the progression of HTN.
C-Reactive Protein (CRP)
CRP is an inflammatory marker and is increased in several conditions like diabetes. 14 Normally minimal amounts of CRP is present in plasma and the level increases to 100 fold when there is any injury, infection, or inflammation. CRP is the first acute phase protein to be described. 15,16 It is mainly synthesized by liver in response to interleukin-6 and interleukin-1ß. Its relation to essential HTN is extensively studied. 17-19 Sesso et al. in their study demonstrated that with increased levels of CRP, risk of developing HTN increases. 18 Similar findings were shown in another study by Wang et al. 20
CRP Increases the Blood Pressure by Various Mechanisms
- It decreases the production of nitric oxide by endothelial cells,21,22 and thus indirectly inhibits vasodilatation.
- It increases leukocyte adhesion, platelet activation, oxidation, and thrombosis. 21,22
- It also up regulates the angiotensin type-1 receptor, thus mediating the angiotensin-II mediated increase in blood pressure.
CRP is very stable and have half-life of 19 hours with very little variation in values between fresh and frozen forms. 23,24 Also it has a longer plasma half-life making it more reliable indicator of chronic inflammation. 25 The only drawback is that it is not detectable at a very low level (i. e. , CYTOKINES (IL-6, TNF, etc)
Cytokines are signalling proteins, which regulate a wide range of biological functions including innate and acquired immunity, hematopoiesis, inflammation and repair, and proliferation through mostly extracellular signalling. They exist in broad families that are structurally related but exhibit diverse function (e. g. , TNF, IL-1, IL-6, etc. ). 28
IL-6 is a central mediator of the acute-phase response and a primary determinant of hepatic production of CRP, plus, IL-6 modulates the production of tumor necrosis factor and regulates the immune response. 29 Circulating IL-6 also stimulates the hypothalamic– pituitary–adrenal axis, which, when activated, is also associated with hypertension. 30 Several factors predispose IL-6 production, including infection, interferon-γ, and TNF.
There are studies that have demonstrated increased cytokine (IL-1β, IL-6, TNF-α) levels in hypertensive patients compared to normotensive patients. 31, 32,33, 34 The link between cytokines and hypertension maybe:
- Various hemodynamic changes due to hypertension leads to endothelial dysfunction, and increase in levels of inflammatory markers such as interleukin-6 (IL-6), intracellular adhesion molecule 1 (ICAM1), P-selectin, and tumor necrosis factor-α (TNF-α). 12,13
- The renin-angiotensin system and sympathetic nervous system, play an important role in regulating blood pressure. They stimulate the release of proinﬂammatory cytokines (IL-6, TNF- α) and serve its source. 35,36 These cytokines in turn induce structural as well as functional alterations in endothelial cells. 36, 37
- CRP by stimulating monocytes also release pro-inflammatory cytokines such as IL-6, IL-1𝛽 and TNF-𝛼 which further promotes inflammation and effects endothelial function. 38
- There is increasing evidence that excess adiposity, which is a major risk factor for hypertension, is characterized by broad inflammatory response 1,39 This induces adipose tissue to release various cytokines and adipokines proteins40 and to create a chronic state of inflammation that may lead to hypertension.
Uric Acid (UA)
Uric acid is a by-product of purine metabolism produced in blood from endogenous purine substances (2/3) or from diet (1/3). 41 It is 5% plasma protein bound, is freely filtered at the glomerulus, is 99% reabsorbed in the proximal tubule, secreted by the distal tubule, and subjected to considerable post secretory reabsorption. Fractional secretion of uric acid is about 7% to 10%. 42 Serum UA serves as a useful marker of inflammation and oxidative stress in HTN. 43 An elevated UA level is observed in nearly 90% of adolescents with essential hypertension of recent onset. 44
A lot of studies have shown a significant association between uric acid levels, HTN and its cardiovascular complications in their study. 45,46 A study by Feig et al. found that by administering drugs that reduce uric acid level such as allopurinol in obese adolescents with pre-hypertension, resulted in marked BP control and reduction in systemic vascular resistance. 47 Scheepers et al. in their study have also focussed on importance of uric acid and purine catabolism, and their potential association with essential hypertension. 48 Association between hypertension and increased UA was first seen in 1957. 49 This raised the question whether increased UA and HTN had a link.
UA is thought to play a role in HTN via mechanisms like inflammation, vascular smooth muscle cell proliferation in renal microcirculation, endothelial dysfunction, down regulation of nitric oxide (NO) production and activation of the rennin – angiotensin – aldosterone system. 50,51 This hypertension type is salt‑resistant in that it occurs even in the presence of a low‑salt diet, and it responds to lowering of UA. 51 The role played by UA in pathogenesis of early onset HTN decreases with increase in age, where stiffening of the aorta, activation of the renin-angiostensin system and renal vasoconstriction have a role to play. 52 This may be the probable reason why many studies found a higher mean UA concentration in pre-hypertensives who were averagely younger. 46, 51, 53
Urine Albumin Excretion(UAE)
The detection and quantification of albumin in urine is commonly used for screening of diabetic and hypertensive nephropathy, as well as preeclampsia. It’s an early marker of renal damage. 54 UAE predicts the development of hypertension, independent of BP and other widely known risk factors for development of hypertension. 55 There are studies which found risk of developing HTN was highest with increase in UAE. 56 This can be explained by following mechanisms:
- UAE reflects damage to the renal microvasculature which causes generalized endothelial dysfunction, thus causing hypertension. 57,58
- Reduction in number of nephrons also provides a link between higher albumin excretion and the development of hypertension. 59
- GFR is mildly reduced when there is reduction in glomerular filtration surface area thereby limiting excretion of sodium and causing hypertension. 60
Nitric oxide is generated from its precursor L-arginine by nitric oxide synthase (NOS). Inflammation has been shown to downregulate NOS activity. 61 Research data suggests impaired NO activity is associated with HTN. Increased ROS and an altered balance between NO and ROS lead to impaired bioavailability of NO, resulting in decreased endothelium-dependent vasodilation, which, in turn, causes or exacerbates hypertension. 62,63 Impaired NO dependent vasodilation due to an imbalance between vasoconstrictors and vasodilators precedes hypertension. 64
HTN is a chronic disease which causes severe complications like CAD, heart failure, stroke, etc. The conventional office or clinical measurement of blood pressure is not enough to diagnose HTN because of its silent nature. Various biomarkers are studied to diagnose prehypertension progression and pathophysiology, but their use in routine practise raises a question. The development of HTN and prehypertension is characterized by an increase in the activity of biochemical markers of endothelial dysfunction like CRP, cytokines, UA and NO.