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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] 1 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] 2 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 3 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 4 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 5 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 6 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) 7 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 8 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 9 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. 10 References: 1. 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