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Strategies to Test for Rheumatic Heart Disease

Rheumatic heart disease remains a major public health problem in many parts of the world. While the incidence and prevalence of ARF and RHD have been decreasing in developed countries since the early twentieth century, they continue to be major causes of morbidity and mortality among young people in developing nations. It is estimated that there are more than 15 million cases of RHD worldwide, with 282,000 new cases and 233,000 deaths annually[1].
Globally, India contributes nearly 25%-50% of newly diagnosed cases, deaths, hospitalizations and burden of RHD.The earliest reporting of RHD was done in 1910. Even during the 1980s, hospital admission data suggested that RF and RHD accounted for nearly one-half to one-third of the total cardiac admissions at various teaching hospitals all over India. A more recent survey across various tertiary care hospitals found that hospital admission rates of RHD had declined (5%-26% of cardiac admissions). Population-based epidemiological data to ascertain the prevalence of RHD and their impact on community in India are lacking. A properly planned population study in 1993 reported a prevalence of 0.09% for RHD.
Most of the epidemiological studies are school-based surveys. The reported prevalence of RHD varied from 1.8 to 11/ 1000 schoolchildren (average 6/1000) during the 1970s and 1980s, and 1-3.9/1000 during the 1990s.Studies using echocardiographic validation of clinical diagnoses show a much lower prevalence of RHD. The surveys conducted by the Indian Council of Medical Research (ICMR) also indicate a decline in the prevalence of RHD over decades.
The epidemiology of rheumatic heart disease in India is of special interest as it may help to understand the effects of economic transition on this particular enigmatic disease. Critical appraisal of the published literature suggests the possibility of a real decline in the occurrence of the disease in some parts of the country, but a continuing onslaught in several other regions. The rate of decline seems to correlate more with improved public health facilities than with economic growth alone. However, the cumulative burden of the disease remains high, and sustained efforts for the prevention of rheumatic heart disease needs special attention [2].
Rheumatic fever is the most common cause of mitral stenosis. Other less common etiologies of obstruction to left atrial outflow include congenital mitral valve stenosis, , mitral annular calcification with extension onto the leaflets, cor triatriatum, rheumatoid arthritis, systemic lupus erythematosus, left atrial myxoma, and infective endocarditis with large vegetations. Pure or predominant MS occurs in approximately 40% of all patients with rheumatic heart disease and a past history of rheumatic fever. In other patients with rheumatic heart disease, lesser degrees of MS may accompany mitral regurgitation (MR) and aortic valve disease. In temperate climates and developed countries, the incidence of MS has declined considerably over the past few decades due to reductions in the incidence of acute rheumatic fever. However, it remains a major problem in developing nations, especially in tropical and semitropical climates[3].
In normal cardiac physiology, the mitral valve opens during left ventricular diastole, to allow blood to flow from the left atrium to the left ventricle. This flow direction will be maintained as long as the pressure in the left ventricle is lower than the pressure in the left atrium and the blood flows down the pressure gradient. Mitral stenosis (MS) is a mechanical obstruction during blood flow from the left atrium to the left ventricle. Obstruction happens due to thickening and immobility of the leaflets, thickening and fusion of the chorda tendinae or mitral annular and commissural calcification[4].
In rheumatic MS, the valve leaflets are diffusely thickened by fibrous tissue and/or calcific deposits. The mitral commissures fuse, the chordae tendineae fuse and shorten, the valvular cusps become rigid, and these changes, in turn, lead to narrowing at the apex of the funnel-shaped (“fish-mouth”) valve. Although the initial insult to the mitral valve is rheumatic, the later changes may be a nonspecific process resulting from trauma to the valve caused by altered flow patterns due to the initial deformity. Calcification of the stenotic mitral valve immobilizes the leaflets and narrows the orifice further. Thrombus formation and arterial embolization may arise from the calcific valve itself, but in patients with atrial fibrillation (AF), thrombi arise more frequently from the dilated left atrium (LA), particularly from within the left atrial appendage.
In normal adults, the area of the mitral valve orifice is 4-6 cm2. In the presence of significant obstruction, i.e., when the orifice area is reduced to < ∼2 cm2, blood can flow from the LA to the left ventricle (LV) only if propelled by an abnormally elevated left atrio-ventricular pressure gradient, the hemodynamic hallmark of MS. When the mitral valve opening is reduced to <1 cm2, often referred to as "severe" MS, a LA pressure of ∼25 mmHg is required to maintain a normal cardiac output (CO). The elevated pulmonary venous and pulmonary arterial (PA) wedge pressures reduce pulmonary compliance, contributing to exertional dyspnea. The first bouts of dyspnea are usually precipitated by clinical events that increase the rate of blood flow across the mitral orifice, resulting in further elevation of the LA pressure.
To asscess the severity of obstruction hemodynamically, both the transvalvular pressure gradient and the flow rate must be measured. The latter depends not only on the CO but also on the heart rate. Increase in heart rate causes shortening of diastole proportionately more than systole and diminishes the time available for flow across the mitral valve. Therefore, at any given level of CO, tachycardia, including that associated with rapid AF, augments the transvalvular pressure gradient and elevates further the LA pressure. The LV diastolic pressure and ejection fraction (EF) are normal in isolated MS.
In MS and sinus rhythm, the elevated LA and PA wedge pressures exhibit a prominent atrial contraction pattern (a wave) and a gradual pressure decline after the v wave and mitral valve opening (y descent). In severe MS and whenever pulmonary vascular resistance is significantly increased, the pulmonary arterial pressure (PAP) is elevated at rest and rises further during exercise, often causing secondary elevations of right ventricular (RV) end-diastolic pressure and volume.
In temperate climates, the latent period between the initial attack of rheumatic carditis and the development of symptoms due to MS is generally about two decades; most patients begin to experience disability in the fourth decade of life. Studies carried out before the development of mitral valvotomy revealed that once a patient with MS became seriously symptomatic, the disease progressed continuously to death within 2-5 years.
In patients whose mitral orifices are large enough to accommodate a normal blood flow with only mild elevations of LA pressure, marked elevations of this pressure leading to dyspnea and cough may be precipitated by sudden changes in the heart rate, volume status, or CO, as, for example, with excitement, severe exertion, fever, severe anemia, paroxysmal AF and other tachycardias, sexual intercourse, pregnancy, and thyrotoxicosis. As MS progresses, lesser degrees of stress precipitate dyspnea, the patient becomes limited in daily activities, and orthopnea and paroxysmal nocturnal dyspnea develop. The development of permanent AF often marks a turning point in the patient’s course and is generally associated with acceleration of the rate at which symptoms progress.
Hemoptysis results from rupture of pulmonary-bronchial venous connections secondary to pulmonary venous hypertension. It occurs most frequently in patients who have elevated LA pressures without markedly elevated pulmonary vascular resistances and is rarely fatal. Recurrent pulmonary emboli, sometimes with infarction, are an important cause of morbidity and mortality rates late in the course of MS. Pulmonary infections, i.e., bronchitis, bronchopneumonia, and lobar pneumonia, commonly complicate untreated MS, especially during the winter months[3].
Mitral valve assessment with echocardiography should include the pattern of valve involvement and calcification, severity of stenosis, associated mitral regurgitation and other co-existent valve lesions and atrial chamber dilatation and function. Mitral stenosis can be assessed in parasternal, apical or subcostal views. As with any stenotic valve the main diagnostic feature in the parasternal long axis view. As in rheumatic MS, the anterior mitral leaflet (AMVL) shows diastolic doming or hockey-stick shape and the posterior mitral leaflet (PMVL) has restricted motion or is totally immobile. This doming is due to the reduced mobility of the valve tips compared to the base of the leaflets. Echocardiography can also adequately assess the Subvalvular apparatus changes such as thickening, shortening, fusion of chordal calcification. Color Doppler in this view with diastolic turbulence across the mitral valve confirms the diagnosis. On the other hand, Parasternal short axis view of the mitral valve is used for assessing the leaflets thickening, fusion and calcification of commissures. The parasternal short axis view is also used to assess the mitral valve orifice area by planimetry of the mitral leaflets at the level of tips. The Following are different means of measurements by echocardiography to ascess the severity of MS. Planimetry of mitral valve at the level of the leaflets tips is done in parasternal short axis view. This method is a very familiar technique by 2D echocardiography but the same method can also be used in 3D echocardiography en-face view of mitral valve. However, newly developed QLAB software in 3D echo is now available for calculation of mitral valve orifice area which requires further validation. Calculation of mitral valve area (MVA) by pressure half-time (P1/2t) should be done in an apical four chamber view using continuous wave. Doppler Pressure half-time method is not valid immediately after percutaneous balloon mitral the Doppler curve. The gradient can be measured by tracing the dense outline of mitral diastolic inflow and the mean pressure gradient is automatically calculated. The severity can be assessed as mild (10) [4].
Both qualitative and quantitative evaluation of valvular heart disease can be improved by 3D echocardiography. Anyplane and paraplane analysis of a stenotic valve allows an accurate planimetry of the smallest orifice area. Zamorano et al demonstrated that 3DTTE is a feasible, accurate and highly reproducible technique for assessing the mitral valve area in patients with rheumatic MV stenosis. In a consecutive series of 80 patients, MV area was assessed by conventional echo Doppler methods and by 3DTTE, and results were compared with those obtained invasively.Compared with all other echo-Doppler methods, 3DTTE had the best agreement with the invasively determined MV area, and intra- and inter-observer variability of the method was very good. Zamorano et al also studied 29 patients undergoing percutaneous balloon mitral valvuloplasty. 3DTTE had the best agreement with the invasively determined MV area, particularly in the immediate post procedural period; therefore, the method could be proposed as an ideal one throughout this procedure and could make invasive evaluation unnecessary in this setting. As part of these very important quantitative data, 3DTTE can be integrated with 2D evaluation in the qualitative morphology assessment of the MV. Commissures, leaflets, annulus calcifications and subvalvular structures can be visualized from different and unique planes facilitating the understanding of this complex apparatus. Vegetations, commissural diseases, subvalvular pathologies (tip of the leaflets/chordae/papillary muscles), clefts can be accurately diagnosed.
So assessment of the severity of mitral valve stenosis requires accurate measurements of the Mitral valve orifice area (MVA). Direct measurement of the MVA can be performed by planimetry using two-dimensional echocardiography (2-D echo). Mitral valve area determined by planimetry reflects the anatomic orifice area and is largely independent of hemodynamic variables, left ventricular compliance and concomitant valvular disease. However, planimetry by 2-D echo requires significant experience and operator skill to define the correct image plane that displays the true mitral valve orifice. In addition, planimetry requires a parasternal short axis view of the mitral valve and is therefore limited to patients with favorable image quality from a parasternal window. To bypass the difficulty of a parasternal short axis view, Doppler traces of the diastolic transmitral flow is obtained from a four-chamber apical view and the mitral valve area is estimated using the pressure half-time (PHT). However PHT is influenced by hemodynamic variables, left ventricular compliance and concomitant valvular disease.
Real-time three-dimensional echocardiography (3-D echo) is a novel imaging technique that is expected to enhance the ability to perform planimetry of the mitral valve. 3D echo utilizes a matrix array echo probe to scan a pyramidal volume in real time. A precise cross-section of mitral valve orifice at the tips of the leaflets with correct plane orientation may provide more accurate assessment of MS severity than two-dimensional echocardiography. Thus it can eliminate one of the principle limitations of 2DE in determining MVA by planimetry. There is less inter- and intra-observer variation also during MVA calculation. Therefore, real-time 3D echo can be used as a practical and accurate method for planimetry of mitral valve areas.
This study will be performed to evaluate the feasibility, reproducibility and accuracy of 3-D echo for the assessment of MVA over conventional 2D planimetry

Carbonic Anhydrase: Structure, Mechanisms and Functions

INTRODUCTION Carbonic anhydrase, abbreviated as CA, is the first identified zinc containing enzyme, (CA; carbonate hydro-lyase, EC 4.2.1.1) It is an enzyme that catalyzes the reversible hydration and dehydration of carbon dioxide to form carbonic acid, bicarbonate ions and protons. Being one of the fastest enzyme known, it is believed that one molecule of CA can process one million molecules of carbon dioxide per second. The basic molecular structure of CA includes specific amino acid threonine 199, glutamate 106, histidine 64 and histidine residues namely His 93, His 95, and His 118. The mode of regulation of CA is being inhibited by various medically prescribed substances that act as non competitive inhibitors, an example is Acetazolamide. CA plays a major key role in the fluid balance and regulatory of pH in different parts of the body thus, Mutation of this enzyme may lead to several diseases.(1)
CARBONIC ANYHYDRASE THE START: Breathing, a fundamental function in life The air that we breathe in has some valuable oxygen, an important molecule wherein it helps the breakdown of fats and sugars in our cells. From the blood, oxygen diffuses then binds with the hemoglobin to be transported in the cells of our body. A by product of sugar and fat breakdown in cells is called Carbon dioxide CO2). It is a key metabolite in all living organism and it needs to be removed from our body.
Carbon dioxide is diffuse out of the cells and transported in the blood in different ways to get to the lungs. CA is transported in numerous forms, mainly as bicarbonate, HCO3-. Bicarbonate is a CO2- with an attached OH group. When the HCO3- reaches the lungs, it is transformed back to a CO2, so it can be exhaled from the body. The conversion of bicarbonate to carbon dioxide facilitates its transport into the cell; while the conversion of carbon dioxide to bicarbonate assists trap the carbon dioxide in the cell. This interconversion of carbon dioxide and bicarbonate develop at a slow physiological pH hence organism tend to produces an enzyme to hasten the process. This enzyme responsible for the speed up interconversion, which can be found in the red blood cells, is called carbonic anhydrase. Although the interconversion of bicarbonate to carbon dioxide can happen without the enzyme, CA can great increase the rate of the conversions up to a millions of fold. (2)
STRUCTURE The CA molecule in general has ellipsoidal shape with the estimated dimension 4.1 x 4.1 x 4.7 nm. The active site is situated in a cavity having an approximately conical shape. The cavity is assessed 1.5 m wide at the way in and about 1.6 nm deep attaining almost the center of the molecule. The zinc ion is next to the peak of the cone and liganded into 3 imidazole groups.
Taken as a whole, the CA is composed of 10-stranded anti-parallel beta-sheet enclosed with various elements of other secondary structure. The 6 alpha-helices and 10-beta sheets make up the secondary structure of carbonic anhydrase. The basic function of CA is basically to regulate the oxygen and carbon dioxide content of the blood that is needed in a human body. As the function suggests, the chemical structure of CA extremely lies with the presence of zinc that lies deep within its active site. Its common amino acid composition includes threonine, glutamate and histidine. The specificity of these 3 amino acids (threonine 199, glutamate 106, and histidine 64) plays a critical role in relation to the presence of zinc by charging it with a hydroxyl ion. The zinc cation is associated with three histidine residue protein backbone namely: His93, His95, and His118. As stated, zinc plays a major role in the reaction of CA. The zinc present in the active side of CA is being bound to water to be able to dissociate it into a proton and hydroxyl ion. The hydroxyl ion is being stabilized by the positively charged zinc, in this way; the hydroxyl ion is being prepared to attack the carbon dioxide inside the RBC.
A closer look with CA can be seen in the figure below where the amino acid chains in the active site together with the zinc are evident. The role of the zinc basically includes the command of directional transfer of the bound hydroxyl to the carbon dioxide to be able to form bicarbonate ion. From the figure, it shows that the intermediate structure where the bicarbonate ion is still attached to the enzyme. The alanine replicated the side chain for amino acid 199 in this arrangement. Histidine 64 swings in the direction of and away from the zinc ion in every cycle of enzyme action although it is helping the zinc to recharge with a novel hydroxyl ion. The two locations of this residue, revealed in the bottom right figure, symbolize its movement throughout the action of enzyme. Almost immediately as the zinc is reloaded with an original water molecule together with the release of bicarbonate ion, the enzyme is set for another action on some new carbon dioxide molecule. (3)
MECHANISM OF CATALYSIS The rate of catalysis of the CA is exceedingly pH dependent. It means that, the higher the pH, the catalysis is faster and as the pH reduces, the speed of the reaction falls down. The mean pH of this transition is near pH 7. (5)
Figure 2.0 shows the mechanism of CA catalysis. A zinc atom which is generally bound to four or more ligands differs in CA. In CA, three locations are engaged by the imidazole rings of three histidine residues and an additional site is occupied by a water molecule. Thus the geometry form of the active site is tetrahedral. The zinc atom plays an important role in the mechanism of CA catalysis because it is responsible for the release of a proton H from a water molecule, which then generates a nucleophilic hydroxide ion. Then carbon dioxide substrate attaches to the enzyme’s active site and is situated to react with the hydroxide ion. The zinc-bound OH- attacks the carbon of CO2 therefore converting it into a bicarbonate ion. This occurs since the zinc ion has the 2 charge, which attracts the oxygen of water. It then deprotonates the water, thus, converting it into a better nucleophile so that the newly converted hydroxyl ion can attack the carbon dioxide. After the nucleophilic attack of zinc bound OH-, addition of water molecule displaces the bicarbonate ion from the metal ion. The CA is then ready for another cycle of catalysis. (7)
KINETICS OF REACTIONS CA inhibitors are class of pharmaceuticals that control the activity of carbonic anhydrase. It is inhibited by two classes of compounds, a metal complex forming anions and others are isosteres and sulfonamides. Inhibitors ionize upon binding with the enzyme to give way an NH- group that relocates the zinc hydroxide ions and shares a hydrogen bond. There are roughly 25 clinically used CA inhibitors as a drugs. It is mainly established as antiglaucoma drugs, diuretics, hypotensive agents, anticonvulsants, anticancer agents, antiepileptics, with additional use in the management of duodenal and gastric ulcers, osteoporosis and neurological disorder. (8)
Acetazolamide
Methazolamide
Dorzolamide
Topiramate
Figure 3. Illustrations of some CA inhibitors (9)
Figure 3.0 shows some CA inhibitors like Acetozolamide which acts as a mild diuretic. It cures glaucoma, altitude sickness, and some benign intracranial hypertension. Methazolamide treats glaucoma present in dogs which is called Open-angle glaucoma. While Topiramate which is a weak inhibitor, alleviate epilepsy, lennox gastuat syndrome and migraine headaches. And another CA inhibitor is the, Dorzolamide or sulphonamide which treat ocular hypertension or open-angele glaucoma. (10)
CA activator regulates the proton transfer processes between the active site and the solvent system. It also binds at the entrance of the enzyme of the active site. One of the strong activator of CA is Histidine. Some amines and amino acids like l-Trp (tryptophan), l-Phe (Phenylalanine), d-DOPA (D- 3,4-dihydroxyphenylalanine), l-Tyr (Tyrosine), 4-amino-l-Phe also works as activators of CA. These CA activators are potentially target for drug development that can be useful as a derivative for the enhancement of synaptic efficacy which can be able to treat various conditions like, depression, alzheimer’s disease, ageing, spatial learning and memory therapy enhancer. (11)
MODE OF REGULATION: Acetazolamide Inhibitor In case of excessive contents of CA in blood and peripheral areas of the lungs, proper regulation and inhibition is needed. Acetazolamide is a non competitive inhibitor that is effective in giving control with the catalytic reaction of the enzyme. This chemical complex substance is medically used o treat different conditions of moderate up to severe metabolic or respiratory alkalosis. Alkalosis may happen if excess CA is being reacted with the bicarbonate and carbon dioxide ions in the RBC, causing extreme absorption of bicarbonate thus giving the erythrocyte more basicity rather than having enough and sufficient pH level. Acetazolamide action is explained by interfering with bicarbonate (HCO3-) reabsorption in the kidneys, thereby giving enough acidity in the RBC, and further results to alkalinizing the urine. The action of inhibition results further to decreased synthesis of aqueous humor of the eye and causes the lowering of intraocular pressure.
The interaction of Acetazolamide with CA does not occur with the active site, only close or remote to the active site. The net effect of this inhibitor basically changes the shape of CA that obviously leads to the inability of the substrate to bind properly, results to no catalytic reaction. (12)
CARBONIC ANHYDRASE IN HEALTH AND DISEASE: Carbonic Anhydrase is found in numerous places in the body, including in the cerebro-spinal fluid, cytosol of some cells and mainly in the red blood cells. Since CA generates and utilizes protons and bicarbonate ions, it plays a major key role in the fluid balance and regulatory of pH in different parts of the body. Absence or mutation of the CA enzyme may lead to several diseases. Also, CA inhibitor contributes to several treatments of diseases.
One of the linked diseases of CA is the Osteopetrosis with cerebral calcification and renal acidosis. It is a syndrome deficient with CA in the body commonly called as Marble brain disease. This happens because sulfonamide inhibitor of CA can produce metabolic acidosis and have shown that CA inhibitors blocks the parathyroid hormone-induced the release of calcium bone which causes bone resorption. And since CA is present in the brain and CA inhibitors inhibits the production of cerebral spinal fluid, mutation of CA lead to cerebral calcification.
Other disease associated with the deficiency of specific type of CAIII is the Myastenia gravis. It is an autoimmune neuromuscular disorder that results to a weak muscle of a person. Defects in CA IV can cause retinitis pigmentosa, a degeneration of retinal photoreceptor, which a patient experiences night vision blindness and loss of midperipheral visual. (13)
Glaucoma, a condition wherein a build up of fluid in the eyes occurs and this presses the optic nerve that caused damage, is treated with the use of CA inhibitors like acetazolamide, brinzolamide, dorzolamide, and methazolamide. These inhibitors lessen the amount of fluid in the eye rapidly by 40% to 60% thus lowering the pressure inside the eye of a person with glaucoma. It now lessens the risk of optic nerve damage which promote vision loss. But prolong use of this drug affects the same enzyme in the tissue and may lead to kidney and liver damage
The CA also plays an important role in the secretion of acid through the catalyzed hydration of excreted CO2 in the stomach lining which is mainly responsible in digestion of food. It helps to make pancreatic juice alkaline and our saliva neutral. In summary, CA performs different role and functions at their specific locations. (14)

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