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 Table of Contents  
Year : 2022  |  Volume : 12  |  Issue : 5  |  Page : 217-223

The laboratory and hypertension - Novel approach for diagnosis and management

Department of Biochemistry, Sir Ganga Ram Hospital, New Delhi, India

Date of Submission12-Jul-2022
Date of Decision28-Aug-2022
Date of Acceptance16-Sep-2022
Date of Web Publication31-Oct-2022

Correspondence Address:
Seema Bhargava
Department of Biochemistry, Sir Ganga Ram Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmrp.cmrp_65_22

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Hypertension remains one of the most significant causes of mortality, affecting more than 1 billion people worldwide. It is a significant public health concern and a major risk factor for renal disease, heart failure, stroke, coronary artery disease and peripheral vascular disease. In more than 90% of hypertensive patients, the cause of blood pressure elevation is unknown. Therefore, early diagnosis and timely interventions are crucial to prevent complications. Over the last four decades, various blood biomarkers have been identified, which can help in understanding the cause of the underlying processes involved in the onset, development and progression of hypertension (HT). It is our attempt, in this review, to suggest a more robust use of circulating biomarkers that may prove to be beneficial in better elucidating the pathophysiology, development, progression and therapeutic efficacy in the management of HT.

Keywords: Biomarkers, hypertension, inflammation, oxidative stress, pathophysiology

How to cite this article:
Bhargava S, Manocha A, Kankra M, Singla P, Sharma A, Datta RR. The laboratory and hypertension - Novel approach for diagnosis and management. Curr Med Res Pract 2022;12:217-23

How to cite this URL:
Bhargava S, Manocha A, Kankra M, Singla P, Sharma A, Datta RR. The laboratory and hypertension - Novel approach for diagnosis and management. Curr Med Res Pract [serial online] 2022 [cited 2022 Nov 27];12:217-23. Available from: http://www.cmrpjournal.org/text.asp?2022/12/5/217/359941

  Introduction Top

The International Society of Hypertension, in collaboration with the American Heart Association and the American Stroke Association, has defined hypertension (HT) as a systolic blood pressure (BP) of ≥140 mmHg (mercury) and/or a diastolic BP of ≥90 mmHg. The global burden of HT is on the increase, like all degenerative conditions. In 2008, 12.8% of all deaths (7.5 million deaths) and 3.7% of total disability-adjusted life years (57 million) were attributable to HT. In 2025, the projection is that 29.2% of the world's adult population will be hypertensive, with the total number increasing by 60% to affect 1.56 billion adults, and 80% of these will be from developing countries. The National Health and Nutrition Examination Survey (NHANES) study of 2007–2012 stratified the population into the age groups of 20–39 years, 40–59 years and ≥60 years. In these groups, the prevalence of HT was 60.4%, 83.8% and 85.4%, respectively, whereas those treated effectively in the same groups were 35.4%, 58% and 54.1%, respectively, indicating that many subjects remain hypertensive, probably due to inadequate treatment. This inadequate control makes it a global cause of morbidity. The morbidity due to HT is attributable to its various sequelae due to the effects of increased pressure in the blood vessels of every organ with a major impact on the heart, the brain, the eyes and the kidneys, resulting in cardiovascular disease (CVD) (including atherosclerosis), renal disease, metabolic syndrome, pre-eclampsia, erectile dysfunction and ocular changes. One of the major problems of Hypertension is that most subjects suffering from the disease may be asymptomatic until one of the complications manifests. Therefore, it becomes important to identify the disease at an early stage to manage it appropriately and prevent (or delay) the occurrence and severity of the complications.[1],[2],[3],[4],[5]

Toward this, guidelines are implemented and updated from time to time by various international bodies. It is our attempt, in this review, to suggest a more robust involvement of laboratory medicine – specifically clinical chemistry – towards early diagnosis, prognosis and management of HT.

  Discussion Top

Ninety-five per cent of subjects with HT suffer from idiopathic or primary essential HT, i.e. a condition with no known cause but associated with multiple risk factors. In contrast, only 5% are attributable to other pathology such as endocrine, renal or vascular pathology or intake of drugs. The contributing risk factors can be broadly classified as genetic factors and environmental influences. The genetic pathology may stem from defects in renal sodium homeostasis, functional vasoconstriction or defects in vascular smooth muscle growth and structure. The events of the pathophysiology of these conditions ramify with each other. Defects in renal sodium homeostasis cause inadequate sodium excretion resulting in salt and water retention and increased plasma and extracellular fluid (ECF) volume with consequent increased cardiac output and HT. Increased ECF volume also causes an increase in the natriuretic hormone, which directly upregulates the vascular reactivity and the vascular wall thickness. These vascular effects lead to increased peripheral resistance and, therefore, HT.[6]

Altered renal sodium handling also acts through the feedback mechanism of the renin-angiotensin-aldosterone system (RAAS). This system is also impacted by genetic alterations in the various isoforms of angiotensin, its receptors (AR1-4), bradykinin, Substance P, angiotensin-converting enzyme (ACE) kininase and several other molecules.[7]

The importance of HT as a cause of morbidity lies in the target organ damage it causes. The major organs affected are the heart, the kidneys, the brain and the vasculature. Hence, it is required that these organ systems be assessed for damage.

This brings us to the question – what are the biomarkers of diagnosis and prognosis? These can be clubbed under the following headings: (a) aetiology and pathogenesis, (b) progression of the disease and (c) complications of target organ damage, as shown in [Figure 1].
Figure 1: The pathophysiology of hypertension can be described in three stages – etiology and pathogenesis, progression, and complications due to target organ damage

Click here to view

  Biomarkers Of Etiology, Pathogenesis and Progression Top

An increase in the vascular inflammatory markers pre-disposes to HT, for example, selections E and P, monocyte chemoattractant protein 1 (MCP-1), tissue inhibitors of metalloproteinases 1 (TIMP-1), fibrinogen, homocysteine, C-reactive protein (CRP) and interleukin-6 (IL-6). The same effect is exhibited by a decrease in the antioxidants such as vascular endothelial growth factor (VEGF) inhibitors, soluble fms-like tyrosine kinase-1 (sFlt or VEGFR-1), selenium, Vitamin C, glutathione peroxidase (GPx) and superoxide dismutase (SOD).

Vascular endothelial growth factor signalling pathway inhibitors and vascular endothelial growth factor receptor-1

The key downstream mediator of the VEGF signalling pathway (VSP) is nitric oxide, which diffuses into the smooth muscle cell layer of the vascular wall and causes vasodilation. VEGF, on binding to its receptor (VEGFR), induces autophosphorylation of the latter. This leads to increased intracellular calcium, which activates calmodulin which in turn binds to and activates endothelial nitric oxide synthase. Recently, VSP has gained prominence as a target for anti-cancer therapy. Inhibitors of the VSP are used to negate the effect of pro-angiogenic factors secreted by solid tumours. They are also used to limit proliferative diseases like those of the retina. These VSP inhibitors have been associated with the development of HT in these patients.[8]

As described above, a decrease in sFlt (VEGFR-1) and placental growth factor, which interacts with VEGFR-1, both of which enable increased synthesis of nitric oxide, would lead to an increased prooxidant state and vasoconstriction.[8]

Tissue inhibitors of metalloproteinases 1

TIMP-1 is a marker of the left ventricular fibrosis and diastolic dysfunction. A study by Lindsay et al. elucidated that plasma TIMP-1, when >500 ng/ml, had a 97% specificity and a 96% positive predictive value for the prediction of diastolic dysfunction in hypertensive subjects when compared to normotensive subjects. Hence, this would be a diagnostic as well as a prognostic marker.[9]


Shankar et al. studied the relationship between plasma fibrinogen concentrations and HT in a population-based cohort of 3654 participants, 49–84 years of age, with a mean age of 61.5 years. They showed that in both men and women, elevated plasma fibrinogen was associated with the prevalence of HT. It was associated with the subsequent development of HT over a 5-year period, even after considering smoking, body mass index, diabetes and BP categories. This was consistent with the findings of the Atherosclerosis Risk in Communities Study.[10]

Monocyte chemoattractant protein 1

In their study on 256 hypertensive individuals, Ritter et al. found down-regulation of circulating MCP-1 levels when HT was accompanied by left ventricular hypertrophy (LVH). This would, therefore, serve as a cardiac prognostic marker in subjects with HT.[11]

Selectins/cell adhesion molecules

The cell-surface expression of selectins (also known as cell adhesion molecules or cell adhesion molecules [CAMs]) modulates the interaction between the endothelium and blood cells in response to pathophysiological stimuli. This is known to lead to the development of atherosclerosis and HT directly. Onozaki et al. subjected cultures of human aortic endothelial cells and human glomerular endothelial cells to cyclic stretch, as evidenced in HT, and then evaluated the effect on the expression of the selectins E, P and L. They found that there was increased expression of only E-selectin in these cultures (47.8 ± 3.4 ng/ml baseline versus 73 ± 12.9 ng/ml after cyclic stretch; P < 0.01). Similarly, De Caterina et al., in their study on 31 hypertensive subjects who were prescribed antihypertensives, showed that serum E-selectin levels were significantly higher in hypertensive subjects than in subjects who became normotensive after treatment (37.4 ± 1.8 ng/ml as opposed to 27.8 ± 0.7 ng/ml; P < 0.001). Thus, E-selectin can also be used as a diagnostic and prognostic marker for HT.[12],[13]

Eikendal et al. conducted a study correlating the CAMs E-selectin, P-selectin, vascular CAM-1, intercellular CAM-1 and lipid profile parameters (total cholesterol, high-density lipoprotein [HDL]-cholesterol, triglycerides and glucose) with the thoracic aorta wall thickness and pulse wave velocity (PWV) as demonstrated by cardiovascular magnetic resonance imaging (CMR) performed on a 3.0 T multi-transmit clinical CMR system. Multivariate regression analysis (after adjusting for age, sex and smoking) revealed the following:

  • P-selectin correlated positively and significantly with aortic wall thickness (P = 0.01)
  • E-selectin correlated positively and significantly with PWV (P = 0.04)
  • vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 did not correlate with the aortic characteristics.

Thus, in young adults, upregulation of P-selectin and, to a lesser extent, E-selectin may mirror atherogenic inflammatory alterations in the vascular bed, enabling early diagnosis and prevention.[14]


Zhang et al. in their prospective follow-up study on 1257 elderly subjects (average age 69 years), used a questionnaire survey, physical examination and laboratory tests as a baseline and followed up these patients for a median of 4.84 years. H-type HT was defined as concomitant HT (BP ≥140/90 mmHg) and homocysteinemia (homocysteine ≥15 μmol/L). Multivariate regression analysis revealed hazard ratios of 2.44 for incident CVD events, 2.07 for stroke events, 8.33 for coronary events and 2.31 for all-cause mortality. Hence, homocysteine, too, could be used as a diagnostic and prognostic marker.[15]

Zhao et al. also elucidated that for every 1 μmol/L increment of plasma tHcy, there was an associated 8% increased risk of all-cause mortality and 7% increased risk of CVD mortality with an adjusted hazard ratio of 1.08 and 1.07, respectively. These data were derived from a cohort of 5724 hypertensive participants with a mean age of 60.7 years of the NHANES database 1999–2002 survey cycle.[16]

C-reactive protein

George et al., in their study including >3500 British women 60–79 years of age, demonstrated a significant association of CRP with systolic BP and pulse pressure. However, this association was markedly reduced when they adjusted for several confounding factors. To further assess the role of CRP, the association of the presence of the polymorphism 1059G to C in the CRP gene (which was expected to lead to raised CRP) with increases in systolic BP was elucidated, and no association was found.[17]

Insulin and renin angiotensin aldosterone system

In subjects with cardiometabolic syndrome, insulin resistance and inappropriate activation of RAAS are one of the major pathophysiological mechanisms related to morbidity, in addition to oxidative stress and inflammation. ACE of the RAAS is directly involved in the development of HT, promoting the formation of angiotensin-II. This latter is the major propagator of the renin-angiotensin-aldosterone-system. Its elevated circulating levels result in HT through its direct effects on the kidneys, causing sodium and water retention and its activation of nicotinamide adenine dinucleotide phosphate oxidase resulting in oxidative stress. In addition, there are several other mechanisms, such as abnormal sodium handling of the kidney, insulin-mediated impaired vasodilatation and enhanced sympathetic nervous system activation.[18]

Atrial natriuretic peptide and brain natriuretic peptide

While causing pathology through increased afterload and pre-load of the cardiovascular system (evidenced by increased circulating levels of atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP]), angiotensin-II also induces a compensatory mechanism-increased secretion of adrenomedullin (AM) which protects target organs from its deleterious effects. The effects of AM are a decrease in vasoconstriction, renin secretion and aldosterone secretion accompanied by an increase in natriuresis. In their 3-year follow-up study, Kato et al. demonstrated that amongst AM, ANP and BNP, AM was the only significant predictor of HT.[19]

  Biomarkers Of Target Organ Damage Top

Hypertension can silently and insidiously affect almost every organ system of the body. However, the major pathological effects are on the vascular system, the heart, the brain and the kidneys.

Vascular damage

As delineated above, the altered expression of fibrinogen, homocysteine, CAMs and selectins E and P herald the beginning of vascular damage leading to HT and the further propagation of the disease if untreated. Therefore, to assess vascular damage, circulating levels of these markers should be estimated.

Cardiac damage

As described above, increases in the selectins E and P, TIMP-1, fibrinogen and homocysteine would be associated with vascular fibrosis, atherosclerosis, and ventricular dysfunction. In addition, the downregulation of MCP-1 is accompanied by LVH. Hence to assess cardiac damage, one should evaluate all these parameters, if available. In addition, concurrent dyslipidemia, specifically high total cholesterol, high oxidised-low-density lipoprotein (ox-LDL) cholesterol, other oxidised lipids, and decreased HDL cholesterol, also pre-disposes to CVD.

Cerebral damage

Hypertension leads to non-specific arteriopathy, enlarged perivascular spaces, and endovascular dysfunction of the small and large vessels of the cerebrum resulting in decreased cerebrovascular reserve, altered autoregulation of cerebral blood flow, and degenerative vascular changes. This leads to microbleedings, subcortical lacunar infarctions, diffuse areas of white matter lesions, and, consequently, manifestations of brain damage (even stroke) and dementia. These would be best visualised on brain imaging to check for microbleeding or microinfarcts, white matter hyperintensity, and large lateral ventricular volume. The biomarkers to assess cerebral involvement would be homocysteine, fibrinogen, VCAM-1 and neuron-specific enolase (NSE). Bharosay et al. in their study including 150 subjects of acute ischaemic stroke, demonstrated that the circulating levels of NSE directly correlated with the neurological worsening and degree of disability.[20],[21],[22],[23]

Renal damage

Those who have controlled and uncomplicated HT have minimal renal impairment. However, those with diabetic/non-diabetic chronic kidney disease (CKD) have an enhanced susceptibility to even moderate increases in BP, which has been demonstrated to be a result of impaired renal autoregulatory mechanisms that protect the glomeruli by attenuating any changes in systemic BP. Thus, 85%–95% of patients with CKD develop HT too. It is important to note that the relationship between CKD and HT is cyclic, one promoting the other and vice versa. Uncontrolled HT is not only a known risk factor for CKD but is also known to be associated with the rapid progression of the condition. At the same time, due to volume expansion and increased systemic vascular resistance, progressive CKD can exacerbate HT. In addition, CKD also pre-disposes to cardiac pathology. To evaluate the extent of renal damage, urinary protein-to-creatinine ratio (UrP/C), urinary microalbumin (UrMab), serum creatinine, serum electrolytes and fractional excretion of sodium (FENa) should be estimated.[24],[25]

  Guidelines Top

The American College of Cardiology, in its 2017 guidelines for the prevention, detection, evaluation and management of high BP in adults, has suggested basic and optional testing:

  • The basic tests include fasting blood glucose, complete blood count, lipid profile, serum creatinine with estimated glomerular filtration rate, serum electrolytes (sodium, potassium and calcium), thyroid-stimulating hormone, urinalysis and electrocardiogram (ECG)
  • The optional testing includes an echocardiogram, uric acid, and urinary albumin to creatinine ratio.[26]

The Ontario Guidelines Advisory Committee of 2019 gave cause-related suggestions for screening tests, as shown in [Table 1].
Table 1: Ontario Guidelines Advisory Committee 2019: Suggested screening tests for selected causes of identifiable hypertension

Click here to view

  The Role Of The Medical Diagnostic Laboratory Top

The current guidelines for the evaluation of HT focus more on management and do not address prevention or evaluation of target organ damage throughout the follow-up. Hence, based on various guidelines as well as published scientific evidence as described above, the following laboratory tests are suggested for proactive diagnosis and management of HT in four proposed situations:

  1. At the time of health check-up – Risk biomarkers should be evaluated if

    • There is a family history of HT
    • History of pre-eclampsia or eclampsia
    • Age >55 years for men and >65 years for women
    • Presence of diabetes/dyslipidemias/family history of pre-mature CVD
    • Sedentary habits/obesity/smoking.

    The investigations suggested at this stage are as follows:

    • Markers of renal sodium handling-Renin, angiotensin I, aldosterone, ACE-II
    • Vascular markers – E-selectin, fibrinogen, vasoconstriction inhibiting factor (VIF)
    • Oxidants and antioxidants such as ox-LDL, lipid peroxides, Glutathione Peroxidase (GPOx), SOD
    • Inflammatory markers – IL-6, CRP.

    Since these are specialised parameters, they may not be available in laboratories catering to only routine investigations. Therefore, it is suggested that estimating two parameters from each group of markers could help assess pre-disposition to HT.

  2. At the time of Diagnosis – all baseline parameters need to be estimated.

    • Lipid Profile, ox-LDL, Lp (a)
    • Renal function tests – serum creatinine, serum electrolytes (sodium, potassium, chloride, calcium), Ur A/C ratio, Ur Mab
    • ECG, Urinalysis
    • Haematocrit, neutrophil-lymphocyte ratio, red cell distribution width
    • Plasma glucose, HbA1c, homocysteine, CRP.

    The above are all available in a routine laboratory.

    In addition, selecting a few of the below parameters would help guide therapy, as given in [Table 2].
    Table 2: Investigations to guide therapy

    Click here to view

  3. At the time of each follow-up – markers of target organ damage should be assessed.

    • Renal markers – UrP/C, UrMab, glomerular filtration rate, serum creatinine, FENa
    • Markers of cardiac status – ANP, BNP, lipid profile
    • Inflammatory markers – IL-6, Tumour necrosis factor alpha (TNF-α)
    • Cerebral markers – homocysteine, cerebrospinal fluid/serum albumin, fibrinogen
    • Vascular markers – GPOx, SOD, sFlt.

    Amongst these, many of the markers are available in routine laboratories except ANP, IL-6, TNF-α, homocysteine, SOD, GPOx and sFlt. However, many specialised laboratories perform the estimation of IL-6, TNF-α, homocysteine, sFlt, GPOx and SOD.

  4. In addition, the following parameters need further clinical evaluation for inclusion in the management of HT – ANP, AM, E-selectin, VEGF, Cathepsin-K, VCAM, NSE, CRP/high-sensitivity CRP (hs-CRP), angiotensin II, ACE-II, aldosterone and 24-h urinary metanephrines. Furthermore, estimating these parameters needs to be simpler and easy to incorporate in routine laboratories.

  Possible Limitations Of The Suggested Protocol Top

The only limitation would be the feasibility of estimating the analytes suggested and how easily their estimation is available in routine laboratories.

Of the suggested analytes, only two require specialised equipment. For example, the estimation of VEGF is done by a flow cytometry-based method which may not be available in most routine laboratories, though most specialised laboratories do house this specialised equipment and perform many tests on it for patient management. The estimation of VIF requires mass spectrometry, which is highly specialised and available in many tertiary care organisations.[27],[28]

The remaining analytes are easily estimated. Several parameters can be estimated by enzyme-linked immunosorbent assay (ELISA). These are selectins, TIMP-1 and MCP-1. However, these assays can be performed only manually and are not yet available on automated ELISA systems.[29],[30],[31]

As for homocysteine, its estimation is now routinely available on automated immunoassay platforms and by ELISA and high-performance liquid chromatography and is being done in most laboratories.[32]

Lipid peroxides (thiobarbituric acid assay), SOD, GPOx, and CRP or hs-CRP estimations are easily available on automated immunoturbidimetry platforms.[33],[34],[35],[36]

  Conclusions Top

To further help early diagnosis and appropriate management of HT, it is suggested that several analytes that are currently infrequently used to be estimated at various stages of assessment of hypertensive patients. Hence, these tests should be incorporated into the approved guidelines to help pre-empt the occurrence of HT or its target organ complications and reduce the morbidity and mortality associated with it.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2]


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