Download 20110609_Manuscript,Role of biosensors in Hypertension

Role of Biosensors in Hypertension
Bhavesh Vinodbhai Patel1*, P. Sam Daniel1, Parloop A. Bhatt2, Ketan M. Patel1, Vijay V. Meghpal1
1
Shri Sarvajanik Pharmacy College, Mehsana
2
L. M. College of Pharmacy, Ahmedabad
*Address for Correspondence
Bhavesh Vinodbhai Patel
Shri Sarvajanik Pharmacy College,
Mehsana-384001,
Gujarat, India.
Phone: +91-9925081277
Email: [email protected]
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Introduction:
INTRODUCTION:
Hypertension is a chronic medical condition in which the blood pressure is persistently
elevated. Systolic blood pressure is greater than 140 mmHg and diastolic blood pressure is
greater than 90 mmHg. Hypertension is a multifactorial disease linked to both genetic and
environmental origins, which ultimately cause direct alterations on the vasculature including
smooth muscle cell proliferation and vascular remodeling. Hypertension requires long life
treatment. Biosensor is a device that detects, records, and transmits information regarding a
physiological change or process. Some biosensors are produce in the body that automatically
decrease or control the blood pressure. High blood pressure is a common risk factor for heart
attacks, strokes and aneurysms, so diagnosing and monitoring it are critically important.
Biosensors are being used increasingly nowadays for the management, control, and diagnosis
for a wide variety of diseases. There are in-vivo parameter which act as a biosensor in
hypertension. These parameter signalling cause and therapeutic approach to treatment of
hypertension. Parameters like baroreceptors nitric oxide, prostaglandin, macula densa act as a
biosensor. This review introduces these biosensor in hypertension. Wearable biosensor
available for continuous monitoring the bloodpressure. Blood pressure can change from
minute to minute, so continuous monitoring offers a much broader picture of cardiovascular
health. The new monitor, which loops around the wrist and the index finger, is just as
accurate as traditional cuff devices but much less cumbersome, allowing it to be worn for
hours or days at a time [1]
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IN-VIVO BIOSENSORS in HYPERTENSION
Baroreflex
Baroreflex or baroreceptor reflex are terms used to describe the body's rapid response system
for dealing with changes in the blood flow regulation system. The human body has its own
physiologic mechanisms for sensing changes in blood pressure and other blood flow changes.
This natural system is largely located in the brain, as well as the walls of the carotid arteries,
which are the vessels in the neck that supply blood to the brain. Pressure sensors, called
baroreceptors, are found on the carotid artery and in the carotid sinus. These sensors measure
and report blood flow to the brain, which compares it to the body’s needs.[2] In a simplified
paradigm, increase in mean arterial pressure (MAP) leads to stimulation of baroreceptors,
which ultimately leads to attenuation of the sympathetic outflow to the peripheral vessels and
the heart. This, in turn, restores MAP to normal levels. Conversely, a decrease in MAP
unloads the baroreceptors and leads to increased sympathetic outflow, vasoconstriction, and
increased cardiac output; MAP is then normalized [3].
Figure 1. A schematic representation of the complex function and multiple interactions
among arterial baroreceptors, cardiovascular system and neural pathways.
The main baroreceptor function consists of blood pressure regulation through a variety of
mechanisms that include modification of the sympathetic output, loss of afferent baroreceptor
stimulus in cases of baroreceptor denervation, baroreceptor resetting and possibly other
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mechanisms unknown at present. Changes of the vascular physiology due to aging,
atherosclerosis, diet, or after carotid endarterectomy alter baroreceptor sensitivity that
subsequently impacts blood pressure and heart rate control. Finally, heart rate changes due to
fluctuations in the parasympathetic activity or altered response to vasoactive medications and
overall baroreceptor sensitivity have an impact on the short- and long-term blood pressure
regulation.
The Baroreflex in Hypertension – Pre-clinical Studies
The baroreflex is a negative feedback mechanism for blood pressure regulation and its
physiology is well established.[4,5] An increase in BP activates the baroreceptors present in
the carotid sinus and aortic arch, which ultimately leads to decreased sympathetic activity in
the heart, peripheral vasculature and kidneys and increased parasympathetic activity in the
heart. These effects lead to a decrease in blood pressure. [6]
While the baroreflex is important in regulating short-term blood pressure changes,[7]
baroreceptors can re-set to a higher activation threshold in response to chronic elevations in
BP[8–10] and also become less sensitive. In one of the preclinical studies carried by
Lohmeier and colleagues the effect of carotid sinus activation on BP regulation has been
investigated in canines it was found that chronic activation of the baroreceptors resulted in an
initial substantial reduction in mean arterial pressure (MAP) and this was maintained for
seven days of baroreflex activation.[11] Reductions in plasma noradrenaline concentration
and heart rate (HR) were also observed. Following termination of the stimulation, the
haemodynamic responses and noradrenaline levels returned to baseline levels.
A Novel Implantable Baroreflex Activation System
Hypertension, a common and serious condition, is the major cause of morbidity and mortality
worldwide. Treatment is generally through administration of antihypertensive medications;
however, up to 15% of patients are resistant to these medications. Resistant hypertension
(RH) often does not respond to aggressive medical therapy, which creates a significant need
for alternative therapies. Carotid sinus baroreceptor activation offers an attractive
alternative.More recently a novel implantable carotid sinus baroreceptor system (Rheos
System®, CVRx Inc, US) has been evaluated. Initial studies with an earlier version of the
device in 11 patients showed that electrical activation of the barorereceptors produced a
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graded voltage-dependent drop in blood pressure.[12] The Rheos System contains bilateral
carotid sinus leads (CSL) and a battery-powered impulse generator (IPG).[13] The IPG is
externally programmable via directional telemetry, allowing the adjustment of stimulation
parameters. The CSL conducts the activation energy from the IPG to the carotid sinuses,
resulting in activation of the baroreceptor fibres present in the carotid sinus wall and,
consequently, activation of the baroreflex.[13,14] The Rheos System works by electrically
activating the baroreceptors, the body’s natural blood low regulation sensors for
cardiovascular function. When activated by the Rheos System, signals are sent through neural
pathways to the brain. The brain sends signals to other parts of the body to reduce high blood
pressure and heart rate and relax the body’s blood vessels.[2]
Working mechanism
Device delivers activation energy through carotid leads wires
Lead wires deliver activation energy to the carotid baroreceptors
Baroreceptors send signal to the brain
Brain send signal to the other body parts to
1. Relax arteries to improve the blood flow
2. Slower the heart rate to allow more time for the heart to fill the blood
3. Reduce the fluid bluid up to reduce the workload on heart.
In brief, on the day of the surgery the patient’s morning doses of antihypertensive
medications are withheld, and aspirin and beta-adrenergic blockers are administered unless
contraindicated. The level of carotid bifurcation is marked on each side using ultrasound
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guidance. A catheter is placed in the non-dominant radial artery for continuous monitoring of
the patient’s BP. The surgical procedure is carried out under general anaesthesia and involves
three stages: anaesthetic induction and exposure of the carotid bifurcation, carotid sinus
mapping and electrode positioning at the location with the highest density of baroreceptors
and lead tunneling procedure (subcutaneously) to the IPG and IPG implantation under the
skin near the collarbone. The patient is seen two days after implantation to check that the
device provides optimal BP lowering. The device is then deactivated to allow wound healing,
and reactivated a month after implantation. Tests are then carried out to determine the most
optimal setting of the device for the specific patient.
Baroreflex Activation in Hypertensive Patients
An early proof-of-concept study was carried out in humans to test whether a Rheos-type
device to activate the carotid baroreflex was a treatment option for patients with
RH.[12]Patients undergoing elective surgery (n=11) for carotid artery surgery were enrolled
in this study. Electrodes were temporarily placed on the wall of the carotid sinus wall and
after obtaining a steady state baseline of BP and HR, an electric current was applied to
activate the baroreceptors. This current was increased in one-volt increments. The results
showed that when the current was acutely applied, a voltage-dependent and significant
reduction in BP was observed.
The European phase II Device Based Therapy of Hypertension (DEBuT-HT) study is an
open-label, single group designed to evaluate the safety and efficacy of the Rheos System in
patients with severe and RH despite treatment with at least three concomitant
antihypertensive drugs. The first published data from the study, in 17 patients with mean
baseline blood pressure of 177/99 and heart-rate of 80 beats/minute showed that system
testing performed one to three days post-operatively resulted in significant mean reductions
in systolic BP, diastolic BP and heart-rate of 28mmHg, 16mmHg and 8 beats/minute,
respectively. At three months post-implant, baroreflex activation produced a durable
response.[13] One year of chronic therapy with the Rheos System in 15 patients resulted in a
significant decrease in resting systolic and diastolic BP and HR compared with preimplant.[15,39] After one year of therapy there was a trend towards decreased BP variability
and increased HR variability, indicating inhibition of sympathetic tone and an increased vagal
tone, respectively. The effect on BP was sustained after two years of chronic therapy in 16
patients with a significant mean reduction for systolic BP, diastolic BP and heart-rate of
35mmHg, 24mmHg and 12 beats/minute, respectively.[16]No unanticipated adverse events
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were reported in the DEBuT-HT study. At one-year, chronic baroreceptor activation did not
impair overall renal function.[17]
Preliminary data from a US phase II study, the Rheos Feasibility Trial, of 10 patients with
RH despite a median of six antihypertensive medications showed that device implantation
was not associated with significant morbidity and no adverse events were attributable to the
device. Three months of active Rheos therapy produced significant mean reductions in
systolic BP and diastolic BP of 22mmHg and 18mmHg, respectively Also An analysis of
combined data from 27 patients from European and US cohorts showed that after six months
of active Rheos therapy systolic BP was significantly reduced by an average of 21mmHg and
diastolic BP was significantly reduced by an average of 16mmHg. A significant reduction in
HR of 9 beats/minute was also observed at six months.[18]
Nitric oxide:
Evidence suggests that nitric oxide (NO) plays a major role in regulating blood pressure and
that impaired NO bioactivity is an important component of hypertension. Mice with
disruption of the gene for endothelial NO synthase have elevated blood pressure levels
compared with control animals, suggesting a genetic component to the link between impaired
NO bioactivity and hypertension. Clinical studies have shown that patients with hypertension
have a blunted arterial vasodilatory response to infusion of endothelium-dependent
vasodilators and that inhibition of NO raises blood pressure. Impaired NO bioactivity is also
implicated in arterial stiffness, a major mechanism of systolic hypertension. Clarification of
the mechanisms of impaired NO bioactivity in hypertension could have important
implications for the treatment of hypertension.[19]
NO is a simple but pluripotent molecule that is predominantly synthesized in the vascular
endothelium. Nitric oxide NO, which is produced from the enzymatic cleavage of l-arginine
to citrulline by a family of NO synthases (NOS), including endothelial NOS (eNOS) and
neuronal NOS (nNOS) (20), has been shown to play an important role in the regulation of
arterial BP (21, 22). In the periphery, endothelial NO acts as a potent vasodilator by
stimulating guanylyl cyclase, which then generates cGMP, inducing smooth muscle
relaxation. (23)
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Figure: 2 Regulation of GC in smooth muscle by NO formed in adjacent endothelium. Akt is
a protein kinase that phosphorylates NOS, making it more sensitive to calcium-calmodulin.
Atrial Natriuretic Peptide
The predominant signal for ANP release is atrial wall stretch or atrial distension due to
volume expansion (24). Atrial stretch, increased heart rate, sympathetic stimulus and
metabolic factors may mediate this effect (25). Endothelin-1, a potent vasoconstrictor of
vascular smooth muscle, induces ANP secretion directly from the heart (26). Endothelin-1
may also mediate atrial stretch-induced ANP release and effects of pressor hormones on the
stress-activated release of ANP (25). Atrial natriuretic peptide exerts its effects by binding to
specific membrane-bound receptors. Three natriuretic peptide receptors have been identified.
The ANPA and ANPB receptors have guanylate cyclase activity and mediate the biological
effects of the natriuretic peptides. The ANPC receptor functions mainly as a clearance
receptor removing ANP from the circulation (27). The main targets of ANP are kidneys and
vascular smooth muscle. It decreases blood pressure due to a direct relaxation of vascular
smooth muscle. In addition, it increases salt and water excretion, enhances capillary
permeability, and inhibits the release or action of several hormones, such as aldosterone,
angiotensin II, endothelin, renin and vasopressin (25). The natriuretic effect results from a
direct inhibition of sodium absorption in the renal collecting duct, increased glomerular
infiltration and inhibited aldosterone production and secretion (28). Atrial natriuretic peptide
therefore counteracts the renin-angiotensin-aldosterone system. Thus, increased adult ANP
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levels are detected in adult congestive heart failure, chronic renal failure and in severe
essential hypertension (25,27).
Prostaglandin
Prostaglandin E2 (PGE2) participates in blood pressure (BP) regulation through diverse
mechanisms involving different tissues and different receptor subtypes. In general, PGE2
functions as a natriuretic factor in the kidney, promoting sodium excretion via inhibition of
sodium transport in the distal nephron. On the other hand, PGE2 is a vasoactive agent capable
of modulating vascular tone.[29]
It is also thought that PGE2 facilitate the ability of kidney to increase the sodium excretion,
thereby protecting the systemic blood pressure from a high salt-diet. However it is not
completely understood how PG system is involved in the salt sensitivity of blood pressure. It
has been reported dilating descending vasa recta (which increase medullary blood flow),
PGE2 enhance the sodium excretion, thereby preventing systemic blood pressure from a high
salt-diet.[31] Although PG involved in the control of efferent arteriolar resistance is not clear
from result we speculated that it may be PGI2 becausePGI2 but not PGE2 exert dilator effect
on the efferent arteriolar (30). On the other hand another possibility based on the finding that
both PGE22 and PGI2 exert antagonizes the vasoconstriction action of Nor-adrenaline and
angiotensin II on pre glomerular afferent arterioles, where by only PGI2 but not PGE2 post
glomerular afferent arterioles. Increase in the intracellular calcium concentration ([Ca2+]i)
stimulates the PGE2 but not PGI2 release, while changes in the extracellular calcium ion in
vivo may selectively alter renal PGI2 synthesis. This raises the possibility that a high dietary
NACL intake may increase intracellular [Ca2+]i in the renal glomerular which in turn may
cause a great increase in PGE2 versus PGI2.[31] Macula densa (MD) cells of the
juxtaglomerular apparatus (JGA) are salt sensors and generate paracrine signals that control
renal blood flow, glomerular filtration, and release of the prohypertensive hormone renin.
The macula densa (MD) is a unique group of approximately 20 sensory epithelial cells in the
distal part of the renal tubular network in close association with the glomerulus, the filtering
unit of the kidney. These cells play a pivotal role in physiologic feedback mechanisms,
sensing changes in tubular salt content and generating and sending paracrine chemical signals
to adjacent contractile vascular smooth muscle and specialized endocrine-like cells that
produce the prohypertensive hormone renin. The MD and these effector cells form the
juxtaglomerular apparatus (JGA) and control important organ functions, including renal
blood flow, GFR, and renin release.[32–34] The sensory MD cells are strategically positioned
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in the JGA with their apical membrane exposed to the tubular fluid, whereas their basilar
aspects are in contact with the JGA effector cells. Elements of the MD control of renin
release include, at least, the activation of p38 and extracellular signal–regulated kinases 1/2
(ERK1/2), mitogen-activated protein kinases (MAPKs), and cyclooxygenase-2 (COX-2) [35,
36] and the synthesis and release of prostaglandin E2 (PGE2) acting on adjacent reninproducing JG cells[37].
NON INVASIVE BIOSENSORS
Ring sensor and smart shirt are the two type of non invasive wearable biosensor which are
used for continuous monitoring of blood pressure. Ring sensor detects blood volume in the
finger changes with the heart muscle expansion and contraction. This blood volume changes
can be easily detected by photoelectric method. Light emitted from the LED is passed
through finger and is directed to photoresistor. Optical density of blood depends on blood
volume. If the blood volume increases, optical density of blood increases, light transmission
through finger reduces and the resistance of photo resistor increases. Thus the voltage
generated by the photo resistor varies with the amount of blood in the finger.
The Smart Shirt can monitor a wide variety of vital signs such as heart rate, EKG,
respiration, and blood pressure Still a prototype, the Smart Shirt uses electro-optical fibers
embedded in the fabric to collect biomedical information. The information is sent to a
transmitter at the base of the shirt where it is stored on a memory chip or sent to your doctor,
coach, or personal server via a wireless network like Bluetooth, RF, wLAN, or cellular.[38]
Conclusion
Biosensors are beneficial for controlling as well as reduction of blood pressure. Biosensor are
useful for long term treatment of hypertension. Biosensors also give signalling for the causes
of hypertension. Finally conclusion is that different biosensors are useful in treatment as well
as diagnosis of hypertension by specific mechanism.
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38. Wearable Biosensor Avaliable:
http://www.edutalks.org/seminars/slides/wearable%20biosensors.pdf
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