3

3. REVIEW OF LITERATURE Hypertension is a chronic, non- communicable, life threatening medical condition .It is preventable & modifiable disease, if not addressed at the earliest it can progress over the life span and cause complications like myocardial infarction, stroke and renal failure and other end organ damage. 2,6,18 Due to the rising prevalence & interplay of genetics and modifiable lifestyle risk factors in its causation, the disease has grabbed the attention of researchers and health care providers. Many studies have been undertaken to assess the knowledge & awareness about the disease in general population all over the globe and also to study its prevalence, risk factors etc.

In recent times, literature on hypertension have elaborated upon the role of genetics in acquiring essential hypertension & its long term complications like impairment of neuro-cognitive functions in children with parental history of hypertension. It is well documented fact in many studies that these children exhibit autonomic dysfunction in the form of sympathetic hyperactivity & slowing down of parasympathetic activity. 3, 4, 6, 14, 23,24 Autonomic nervous system via sympathetic branch , that helps an individual in tackling fight-flight situation ,mainly regulates BP & is excitatory to heart and blood vessel causing rise in HR, cardiac contractility & vasoconstriction. Parasympathetic branch i.e., inhibitory innervations via vagus nerve, regulates cardiac function. It decreases HR & cardiac contractility mainly during emotional state. Cardiovascular system fails to control cardiac and vasomotor sympathetic drive associated with many cardiovascular diseases like hypertension and leads to worsening of the condition if autonomic imbalance occurs in the form of excessive sympathetic excitation and slowing down of parasympathetic activity.25
This sympathetic reactivity in the form of high blood pressure has a negative impact on neuro-cognitive functions in long run. 17 The impact of hypertension on cognition has been studied by many researchers using audiovisual reaction time and its validity as one of the reliable & age old standard test to assess cognition (like alertness, quickness, decision making) and sensory motor function has been documented. 26, 27
Stress and anxiety act as important risk factors in pathogenesis and progression of hypertensive state/ the disease outcome & the same is confirmed by many studies. 20, 28
Hamilton Anxiety Rating Scale is a subjective assessment scale (HAM-A) that is validated as a reliable Questionnaire to assess anxiety levels in many studies.29 The studies on children with family history of hypertension also highlighted upon the importance of periodic evaluation of high risk groups, early diagnosis and lifestyle modification in them, so as to halt the progress of the disease and reduce the disability adjusted life years associated with high blood pressure. 30
Blood pressure “is defined as the lateral pressure exerted by column of flowing blood on the walls of arteries”. Blood pressure usually measures mean arterial pressure. The blood pressure measured at anytime of the day is defined as casual blood pressure & if recorded in the basal state (complete physical & mental rest & after 12 hrs of fasting) is called basal blood pressure. 31
Landmarks in the history of hypertension:
‘Hard pulse’, an ancient term used in India’s Ayurvedic and China’s medicine literature, was an old method used by experienced physician to assess the working of cardiovascular system by gently palpating the radial pulse. In recent times it came to be termed as ‘Hypertension’. The concept of hypertension & essential hypertension in detail for the first time was given by an Irish-Indian physician working from Guy’s Hospital, London , Frederick Akbar Mahomed (1849–1884).He also demonstrated that high BP was more commonly recorded in older population. He also found that younger individuals exhibited high BP that affected heart, kidney and brain in long run. The modern quantitative concept of hypertension came into existence in early 20th century, following invention of mercury sphygmomanometer and definition of korotkoff sound in which appearance and disappearance of sounds were SBP/DBP respectively.
‘Hypertension’ as a disease, came to limelight following the death of US President F.D. Roosevelt. The cause of death was later diagnosed to be raised BP, that was recorded in him 2 months prior of him suffering from fatal hemorrhagic stroke. Following this incidence many insurance companies in USA made measurement of BP mandatory in general physical examination. After 3 years following the death of F.D. Roosevelt, National Heart Act was signed by the then US president Truman, which paved way for many researches in cardiovascular studies like Framingham Heart Study. Actuarial Society of America, on the basis of their large scale researches pointed out that high BP/ hypertension is associated with high morbidity and mortality. 32Definition of hypertension by JNC VII:
Hypertension is defined as sustained blood pressure ?140 mmHg of SBP ; ?90 mmHg of DBP (JNC VII, 2003).Further JNC VII categorized hypertension as Stage I ,where in SBP/DBP is 140-159mmHg/ 90-99 mmHg and Stage II in which SBP is ?160 mmHg ; DBP is ?100 mmHg. The report also observed that when the blood pressure ranged between 115/75mmHg to 185/115 mmHg, with every increase of 20/10 mmHg recording, the cardiovascular risk doubles. Pre hypertension state is defined as SBP/DBP between 120 – 139/80 – 90 mmHg. It also highlighted upon significance of lifestyle modification in individuals with pre-hypertension in the form of salt restricted diet, regular exercise etc. 33
Prevalence of hypertension with respect to world and India:
The data on prevalence of hypertension across the world noticed some significant observations. Global Health Observatory of WHO noticed that prevalence of hypertension in adults of ?25 years of age was found to be 40% in 2008 all over the world. The highest prevalence of hypertension was found in WHO region of Africa around 46% (including both sexes) ; lowest prevalence was recorded from WHO region of America accounting for 35% (in both sexes).On the basis of income, prevalence was found to be high in low, lower-middle ; upper-middle income group countries (around 40%) ; lowest prevalence of hypertension was recorded from high income countries (35%).Studies in India on prevalence of hypertension found that urban population showed highest prevalence of hypertension ; rural population is exhibiting rising trend in recent years for the same. Overall crude prevalence of hypertension reported from India ranges between 30-50%. 4, 34
Risk factors for hypertension:
The sudden and drastic rise in prevalence of hypertension all over the world, affecting both developed ; developing nations is attributed to rapid urbanization ; globalization. 35 This changed face of global economy has also imposed excessive stress on working population in the form of altered work pattern like shift works, long hours of work ; has forced us to adapt to sedentary lifestyle. The work related stress along with sedentary life style and other risk factors like changed dietary pattern in the form of consumption of high fat ; calorie rich diet with less fibers as vegetables ; fruits , canned salt rich food with excess consumption of alcoholic beverages ; tobacco smoking has contributed immensely to this rising prevalence of hypertension 2,3,36,37
The major contributor to the disease prevalence is essential /primary hypertension with genetic predisposition, accounting for 80 to 90 % of the cases of hypertension. 38 Rest of the cases are nonessential /secondary hypertension,due to secondary causes elsewhere in the body like renal causes- glomerulonephritis, pyelonephritis, polycystic kidney disease, JG cell tumor and adernocortical causes- hyperaldosteronism, Cushing’s syndrome etc. The risk of developing essential hypertension in children was found to be doubled if both the parents were hypertensive. The common genes, environmental factors & emotions they share within the family are attributed as the underlying mechanism for essential hypertension. 39 , 40
Large numbers of animal experiments were undertaken to explain pathogenesis underlying essential hypertension. They were successful in demonstrating the role of sympathetic nervous system over-activity (SO) which controls circulation and handles renin release from kidney. Abnormalities associated with sympathetic hyperactivity(Fig:1) causes increase in HR, peripheral resistance, CO , increased absorption of sodium in proximal tubule, high sodium-lithium counter-transport & low urinary kallikrein levels in kidneys etc proves its role in regulation of glomerular filtration rate and sodium excretion. These studies also observed SO was associated with increased level of total cholesterol, LDL- cholesterol, triglycerides level with high fat pattern index, increased oxidative stress, body mass index, fasting plasma insulin concentrations & uric acid levels.38,40,41,42,43
FIG 1: EFFECT OF SYMPATHETIC OVER-ACTIVITY (SO) ON DIFFERENT SYSTEMS

Many researches in genetics of primary hypertension have established monogenic hypertension causes like angiotensin-aldosterone system (RAAS) polymorphism. The first monogenic HTN syndrome that was identified was an autosomal dominant inherited disorder called Glucocorticoid-remediable aldosteronism. Later many monogenic mutations of corticosteroidogenic genes e.g., 11 ?-hydroxylase gene (CYP11B1 & CYP11B2) & HSD11B2 gene mutation causing autosomal recessive disorder, the syndrome of apparent mineralocorticoid excess (AME) were identified. Liddle Syndrome (SCNN1B/SCNN1G gene mutation), Pseudohypoaldosteronism Type II (Gordon Syndrome, Familial Hyperkalemic HTN) with WNK 1 & 4 -serinethreonine kinase gene & epithelial sodium channel (SCNN1B, SCNN1G) were other monogenic mutations that were elaborated upon. The discovery of apolipoprotein-L1 gene on chromosome 22 mutation with autosomal recessive pattern of inheritance is a recent development in monogenic study on essential hypertension. 44, 45
Sympathetic nervous system over-activity:
The understanding of sympathetic nervous system goes back to 17th century, when for the first time Thomas Willi (Head Of Neuro-anatomy School) illustrated and published anatomy of sympathetic nervous system in “The Anatomy Of The Brain” in the year 1664(Fig: 2). Its role in controlling compliance of blood vessels was demonstrated by Pourfoise du Petit (1727) in experimental animals by dissecting cervical sympathetic nerve which led to conjunctival vessels dilatation. These vasomotor fibers were identified as sympathetic efferent nerves by Stelling in 1840.These nerves were later on named as “pressor nerves” (as their stimulation caused vasoconstriction & severing led to vasodilatation) by Claude Bernard, Waller & Brown-Sequard. They were the pioneers in explaining its role in causation of hypertension. 46
FIG 2: DIAGRAMMATIC REPRESENTATION OF ANATOMY OF SYMPATHETIC NERVOUS SYSTEM IN “THE ANATOMY OF THE BRAIN” -BY THOMAS WILLI IN THE YEAR 1664

Hans Selye (in 1930) explained the role of SNS in flight/fight response to stress. Further Adrian , Bronk & Phillips added on to its role in maintaining vascular tonic discharge that regulated cardiovascular function not just during stress ,but also in resting state. Unique feature of these fibers was they got activated in groups on stimulation & discharged in a synchronized fashion. This discharge occurred in rhythmic manner with each cardiac rhythm. The old theory of role of baroreceptor afferent input in regulating rhythmic discharge is elucidated now along with sympathoinhibitory & Sympathoexcitatory stimuli arising from of carotid body, aortic arch , cardiopulmonary baroreceptors and peripheral chemoreceptor’s/ primodal cardiovascular low threshold receptors respectively.
Large numbers of experimental studies in both animal ; humans till date have successfully come up with role of sympathetic neuronal abnormality in initiation, maintenance ; progression of the primary hypertension. Sympathetic over activity response to stressful stimuli in the form of abnormal cardiopulmonary, chemoreflex abnormality with high adrenergic response and excess outflow of norepinephrine to the blood vessels of heart, renal ; skeletal muscle were elaborated in these studies. Positive family history of hypertension is seen to be associated with excessive nor epinephrine spillover, wherein 50% of essential hypertension cases were found to exhibit neurogenic cause. 46, 47
Pathophysiological basis for sympathetic over-activity:
Various models have been proposed to explain autonomic dysfunction and sympathetic hyperactivity in causation of neurogenic hypertension. Three mechanisms acting as positive feedback-loop mechanism causing sympathetic hyperactivity and autonomic dysfunction were found to activation of AT1 receptors, inflammatory constituents ; oxidative stress. These factors bring about abnormalities in baro-receptor reflex mechanism, remodelling of brain arterioles leading to cerebral ischemia (brain vasculature hypertrophy remodelling) and peripheral chemo-sensitive cell activation via increased pro-inflammatory cytokines. The latter was experimentally proved by denervating carotid body that contain inflammatory mediators (like TNF?, IL I?, HMG B1) in paraventricular nucleus (PVN) ; nucleus tractus solitarius (NTS).
Another model for sympathetic hyperactivity-autonomic dysfunction was explained by Ang II induced AT1 receptor-Brain Renin-Angiotensin System activation in neurons and glial cells. This causes activation of NADPH oxidase via protein kinase C (PKC), releasing superoxide. Superoxide in turn activates redox sensitive pathway. e.g., Mitogen activated protein kinase (MAPK).This increases gene expression for pro-inflammatory cytokines, NADPH, oxidase subunits and RAS component via stimulation of nuclear transcription factor (NF-KB ; AP-1).
An alternate explanation for sympathetic over activity by Robin Davisson agrees with above theory till production of superoxide via NADPH oxidase .Further he explains that superoxide causes activation of glutametargic NMDA mediated Ca2+ influx and neuro-activation. The excessive oxygen species, antioxidants and nitric oxide donor’s abolish Ca2+, thus reduces the bioavailability of nitric oxide and causes nitrosylation of NMDA receptor subunit-NRI and leads to increased sympathetic activity. 48
Tests to assess sympathetic nervous system:
Tests to assess sympathetic nervous system can be classified as invasive and non-invasive tests. Non-invasive tests are QT/QS2 Ratio, sympathetic skin response (SSR), isometric hand grip test (IHG-test) & cold pressor test.49 Newer techniques to assess rate of sympathetic neurotransmitter release like radiolabelled noradrenaline, an isotope dilution methodology have replaced old methods like measurement of excretion of sympathetic transmitters -urinary noradrenalin (Von Euler et al, 1954). In 1968, Hagbarth & Vallbo came up with major development in the form of clinical microneurography technique.In this a fine tungsten electrode tip was inserted through skin and placed in sympathetic fibers. Here the electrode records burst activity of multiunit efferent nerves to skeletal muscle vasculature that are synchronous with each heart beat. It mainly records postganglionic nervous impulses in peripheral nerves, subcutaneous sympathetic firing in nerves distributed to skin & skeletal muscle vasculature. It is a direct measure of muscle sympathetic nerve activity (MSNA) that reflects sympathetic activity related to cardiovascular control of vascular resistance. Single fiber sympathetic nerve recording is the recent development in microneurography study (Macefield et al. 1994). Another sensitive invasive test that detects reflex sympathetic response to exercise and upright posture, diagnosis of autonomic failure syndromes and study of sympathetic drug effect is plasma noradrenaline measurement like total noradrenaline spillover measurements, regional, organ-specific noradrenaline spillover etc . 47, 50
Isometric hand grip dynamometer test (IHG – Test):
A noninvasive test in the form of physical stress test to assess autonomic modulation is isometric hand grip dynamometer test (IHG test). It is a physiological test that is validated to be a reliable test in unmasking pre-hypertension in children with parental history of hypertension. A raise in diastolic blood pressure in response to it is considered as sympathetic over-activity (there is no cut-off limit for rise in DBP on IHG Test, rise up till). Compression of IHG dynamometer creates high tension in the exercising muscle that raises pressure in arteries by pressor stimuli to cardiovascular system & increases CO, HR and peripheral resistance. 6, 18 Isometric or static exercise is one that increases muscle tension, with little or no change in its length e.g., lifting heavy weight, pushing against wall. In contrast to this, isotonic or dynamic exercise causes change in length of the muscle e.g., running, swimming etc.24 Sustained handgrip test is the only available test that measure efferent reflex sympathetic pathway damage & also fulfils the criteria to be a useful test in assessing autonomic function & evaluation of autonomic damage. 51
Audiovisual reaction time:
Reaction time or response latency is the time interval between a given stimulus and initiation of an appropriate voluntary response in a given subject(S-R interval). It measures sensory-motor coordination and processing of stimuli by higher centre. It is reliable non-invasive test that indicates rate of processing of sensory stimuli and execution of motor response. It assesses quickness, intelligence, alertness, arousal level and decision making ability of a person.52, 53,54 Reaction time is measured in a variety of psychological experiments. Historical development in understanding and measurement of reaction time for first time was elaborated in the paper ‘The Calibration of Minds and Machines in Late 19th Century Psychology’ by Ruth Benschop and Douwe Draaisma (of the Department of History and Theory of Psychology at the University of Groningen, Netherland) .Further development in understanding its working was given by F. C. Donders in 1865, a Dutch physiologist, pioneer in reaction time research. He worked upon the methods to measure the time required for the basic mental processes, as they were too fast to be measurable.
Donder’s experiment comprised of giving electrical shock to the subjects, to which they responded by pressing a telegraphy key either by using left or right hand. In one experiment the subjects were made aware of stimuli beforehand and in another experimental condition the subjects were unaware of to which feet stimuli shall be given. The difference between the two conditions was found to be 1/15 second .The duration of a well-defined mental process was determined by Donder for first time,that reflected decision of choice and will of response action to the given choice. He thus showed through his experiments that simple reaction time was shorter than recognition and choice reaction time. And choice reaction time was found to be longest one.

Donders work on reaction time was facilitated by work of Englishman Charles Wheatstone in 1840, who had invented a device that measured velocity of artillery shells. The device was based on principle of his own work electric telegraphy system, where in an electrical signal started or stopped the gun. On giving stimuli the projectile left the gun-muzzle and device was stopped electrically on striking target. Later the reaction-time measuring trial was further helped by “The clockwork mechanism of the Hipp Chronoscope” (named after a Swiss watchmaker Mathias Hipp, in 1842). Donder’s work was further taken forward by Wilhelm Wundt, who built a research laboratory for measuring time taken for processing various mental processes. His area of interest to measure psychological processes or “MENTAL CHRONOMETRY” was a central issue during 1870’s till 1950’s and has influenced in designing of many psychological experiments for precise measurements of reaction time.This elaborate work was penned by him in his book ‘Grundzuge der physiologischen Psychologie’ appeared in 1873.Later on instruments like control hammer and chorography were developed to measure reaction time.55
In 1968 Laming gave average time of simple reaction time as 220 ms and recognition reaction time as 384msec.The accepted mean simple reaction for young college age population since around 120 years is 190 ms (0.19 sec) for light stimuli and 160 ms for auditory stimuli. Many researchers till date have supported the finding that reaction time for sound is shorter than light stimuli, mean auditory reaction time ranged between 140 – 160 ms and visual reaction time is 180 -200 msec. Reaction time for touch is intermediate i.e., 155 msec. Different kinds of reaction time experiments have been explained by psychologists, they are simple reaction time, choice reaction time, recognition reaction time. In simple reaction time only one response to one stimulus is used. E.g reaction to sound, spot a dot etc. Simple reaction time (SRT) tests first studied by Francis Galton in the late 19th century.In choice reaction time experiment user must give response in correspondence to stimuli e. g pressing a key corresponding to a letter response to that particular letter. Recognition reaction time experiment is one where some stimuli need to be responded and others should be neglected (the detractor set) e. g tone recognition, symbol recognition.
Reaction time is affected by various factors like age, gender, right and left handedness, direct and peripheral vision, fatigue, personality type, intelligence, exercise, Stress and anxiety.
Age & gender is found to affect reaction time. In infancy the reaction time is found to be longer that shortens in 20’s and again goes on increasing in 50’s and 60’s.The lengthening is accelerated after 70’s and thereafter. With age recognition and choice reaction time both are affected. It is seen that males have faster reaction time than females. This disadvantage in females is not reduced by practice. The explanation given by many studies for this gender difference was that, men were more into sports and have strong musculoskeletal mass than females. Many studies in recent times have found that male advantage of visual reaction time being shorter is reducing now as women are more into sports and their participation in driving and fast action sports is increasing. Mean reaction time in males was found to be 220ms and in females it was 260ms .For sound stimuli in males mean reaction time was 190 ms and females had 200ms. Another interesting finding noticed in many studies is age related impairment in reaction time was same for both the genders.

Left and right handedness also affects RT. The right hemisphere controls left hand and vice-versa. This difference made researchers to find out does handedness affect reaction time? Some studies have concluded that left handedness has inherited advantage over right handedness. They also found that RT was shorter in right handed males than right handed females and this was not true for left handedness in both the genders. It was also found that preferred hand was generally quick than non preferred hand.

Central & peripheral vision is also affects RT. It is seen in many studies that visual stimuli falling on different part of retina produce different reaction time. Reaction time was faster when stimulus was perceived by cones compared to the stimulus falling on rods. Stimulus intensity affects reaction time, weaker stimuli has the longer reaction time & vice-versa. Practice also affects RT, individuals performed better on RT when adequate practice was given.

Exercise improves RT i.e., individuals with better physical fitness had faster RT. In some studies sedentary students were found to have slow RT in comparison to students who were active. Fatigue along with complicated tasks is found to be associated with delayed RT. It is also seen that mental fatigue like sleep deprivation has more effect on RT than muscular fatigue where in the former is associated with delayed RT & latter was found to have no effect on RT.

Individuals with high intelligence level were found to exhibit faster RT than individuals with normal intelligence. There was no variation in RT in individuals with similar intelligence. Personality type also affects RT, as extroverts have faster RT than introverts. Some studies found that anxious personalities had faster reaction time. Excessive anxiety levels e.g., before any competition / mental task, impair external performance by causing disorganization of behaviour, which in turn decreases motor performance.56,57 Anxiety is a basic human emotion expressed towards an event that is perceived as a threat to self-esteem or ego and is characterized by fear and uncertainty. Anxiety of moderate level is good for individual’s adaptation and productivity but severe anxiety and arousal interferes with persons capacity to overcome difficulties by provoking fear, causing inhibitions ; somatic changes (like tachycardia, palpitations, sweating, dry mouth, poor concentration) leading to maladaptation and poor academic performance. Studies on panic disorder and high anxiety have found sympathovagal imbalance in these individuals in the form of sympathetic over activity ; parasympathetic hyperactivity. The children with family history of hypertension need early evaluation so as to help them in coping up with professional and personal life challenges.58
Hamilton Anxiety Rating Scale (HAM-A or HARS, 1959):
HAM-A is a clinician based questionnaire. It is one of the first and most widely used validated rating scale to assess perceived anxiety symptoms. In recent times it has been used as a benchmark to devise many other anxiety rating scales.59,60,61 Maier et al in their study concluded that HAM-A and its subscales are sufficiently reliable and validity scale to assess anxiety.60 It was designed with an intent to assess anxiety neurosis (not to assess pathological anxiety or problem).It is now employed as self-scored survey questionnaire ,which is easily available in public domain ; comprises of 14 symptoms – defined elements that cater for both somatic and psychological symptoms. HAM-A is widely used scale for clinical research (for psychological intervention and medication), though has limited usage in evaluating effect of anxiolytics drugs and less effective in discriminating somatic anxiety in comparison to drug induced anxiety. 62, 63, 64, 65