Congenitally, unicuspid, bicuspid, tricuspid, or even quadricuspid aortic valves may be the cause of aortic stenosis. In neonates and infants <1 year, unicuspid valve is the most common anomaly with fatal valvular aortic stenosis. Bicuspid aortic valves do not cause significant narrowing of the aortic orifice during childhood. In

congenital bicuspid aortic valve, there are only two functional cusps, usually of unequal size, with the larger cusp having a midline raphe, resulting from incomplete commissural seperation during development. Less frequently, the cusps are of equal size and the raphe is absent. The raphe is frequently a major site of calcific deposits. The altered architecture of the bicuspid aortic valve induces turbulent flow with continuous trauma to the leaflets, ultimately resulting in fibrosis, increased rigidity, calcification and narrowing of the aortic orifice in adulthood [25] . Congenitally malformed tricuspid aortic valves with unequally sized cusps and commissural fusion called as “functionally bicuspid valves”, can also cause turbulent flow leading to fibrosis and, ultimately, to calcification and stenosis. Clinical manifestations of congenital aortic stenosis in adults usually appear after the fourth decade of life. Stenotic bicuspid aortic valve comes to clinical attention at 50 - 70 years and senile calcific aortic stenosis of tricuspid valve at 70 - 90 years. Degenerative calcific aortic stenosis occurs as a consequence of long-standing hemodynamic stress on the valve and usually manifest in individuals older than 75 years with a prevalence of 2% - 9% and occurs most frequently in males [26] having the risk factors of hypertension, hypercholesterolemia, diabetes mellitus, and smoking, due to active disease process at cellular and molecular level that shows many similarities with atherosclerosis, ranging from endothelial dysfunction to, ultimately calcification. The calcification may extend to mitral annulus and conduction system and produce conduction defects. The age-related degenerative (“wear and tear” of either of anatomically normal or congenital bicuspid ones) calcific aortic stenosis, there is dystrophic and passive accumulation of hydroxyapatite, the same calcium salt that is found in bone [27] . Chronic injury due to hypertension, hypercholesterolemia and inflammation in atherosclerosis differs as smooth muscle cell accumulation from the valve injury of calcific aortic stenosis in which abnormal valves contain cells resembling osteoblasts that synthesize bone matrix proteins and promote the deposition of calcium salts. BAV (bicuspid aortic valve) incur greater mechanical stress than the normal tricuspid valves, which may explain why they become stenotic more rapidly. The morphologic hallmark of non-rheumatic, calcific aortic stenosis (with either tricuspid or bicuspid aortic valve) is heaped-up calcified masses within the aortic cusps that ultimately protrude through the outflow surfaces into the sinus of valsalva and prevent the opening of the cusps. The free edges of the cusps are usually not involved and the commissural fusion is not found as in postrheumatic aortic valve stenosis. The calcific process begins in the valvular fibrosa at the point of maximal cusp flexion near the margin of the attachment and the layered architecture of the valve is largely preserved.

Patients with bicuspid aortic valve may be completely asymptomatic. About 30% of individuals with a bicuspid aortic valve develop complications [28] . Occasionally, a congenital bicuspid aortic valve may be the cause of critical aortic stenosis, with symptoms of severe heart failure, developing in early infancy. This critical form of stenosis is more frequently associated with a unicommissural valve (severe form). The bicuspid aortic valve (moderate form) generally functions well in patients with left heart obstructive lesions such as coarctation or interrupted aortic arch and the incidence of bicuspid aortic valve is >50% in these lesions. [29] . Stenosis of a bicuspid aortic valve is more likely to develop in persons older than 20 years and is caused by progressive sclerosis and calcification. High levels of serum cholesterol have been associated with more rapidly progressive sclerosis of the congenitally bicuspid aortic valve [30] . Children who develop early progressive pathologic changes in the bicuspid aortic valve are more likely to develop valve regurgitation than stenosis. Stenotic or partially fused valves may be caused by inflammatory process such as rheumatic fever.

There is a propensity for premature fibrosis, stiffening, and calcium deposition resulting in significant stenosis and cusp prolapse (due to redundancy of conjoined leaflet [31] ), fibrotic retraction, or dilatation of the Sinotubular Junction resulting in Regurgitation in abnormally functioning congenital bicuspid aortic valves as “valvulopathy”. In addition, patients with poor lipid profile and those who smoke also act as an elevated rik of developing hemodynamically significant bicuspid aortic valve stenosis [32] . Aortopathy refers to dilated aortic root, usually associated with BAV and may lead to aortic aneurysm, dissection (the most feared complication―4%) and rupture due to accelerated degeneration of the aortic media, indicating that BAV disease is an ongoing pathological process and not a discrete developmental event. Certain Gene mutations (NOTCH 1) have been implicated in fibrillin―1 deficiency in tissues. MMPs (matrix metalloproteinases) become activated, degrading the structural support of the aorta and medial weakness, resulting aortopathy in BAV. Recently, it is stated that identification of hemodynamics for leaflet fusion patterns enables detection of specific aortic regions susceptible to dysfunction. Variance in WSS (wall shear stress) and flow displacement are important in aortic leaflet morphology [33] . In BAV, helical and high velocity outflow patterns are consistent with aortic dilatation hemodynamics and RL fusion causes dilation of mid-ascending aorta, while RN fusion is associated with dilation in aortic root [34] as shown in Figure 11, distal ascending aorta and transverse arch are not dilated in this patient. Atherosclerotic aortic valve stenosis occur more frequently in patients with severe hypercholesterolemia and is observed in children with homozygous type II hyperlipoproteinemia [35] (total serum cholesterol >800 mg/dl from birth). Immunohistochemical evidence of chlamydia Pneumoniae has been found in early lesions of age related degenerative aortic stenosis [36] .

Aortic valve may become bicuspid due to an acquired deformity of rheumatic process and have a fused commissure that produces a conjoined cusp as shown in Figure 4 and it is twice the size of nonconjoined cusp.

BAV is the most frequent congenital cardiovascular malformation in humans [37] . Bicuspid aortic valves are responsible for approximately 50% of cases of aortic stenosis in adults [38] . In bicuspid aortic valve, two cusps are seen in systole with only two commissures framing an elliptical systolic orifice. Diastolic image may mimic a tricuspid valve when a raphe is present. Long axis view shows asymmetric closure line and systolic doming. In children and adolescents, it may be stenotic without extensive calcification. Calcification of tricuspid aortic valve is most pronounced in the central part of each cusp and commissural fusion is absent, resulting in a stellate-shaped systolic orifice. Rheumatic aortic stenosis is characterized by commissural fusion, resulting in a triangular systolic orifice with thickening and calcification most prominent along the edges of the cusps as shown in Figure 5.

Bicuspid aortic valve may assume three different types of configuration [39] . Type-1―“Real” bicuspid valve with two symmetric leaflets, Type-II―A tricuspid architecture with a fusion of two leaflets, Type-III―A tricuspid architecture with a fusion of 3 leaflets. Another classification described by Hans Sievens in 2007 based on the number of “cusps” and “raphes” as Type 0―no raphe (pure bicuspid aortic valve), Type-1―1 raphe, Type- II―2 raphes. “Raphe” is the arrow-shaped formation of tissues, also called “false commissures” and refer to the fused areas where the undeveloped cusps form a malformed commissure [40] .

Demonstration of marked eccentricity of the aortic valve diastolic echoes with respect to the aortic lumen appears to be the hallmark of a congenital bicuspid aortic valve. A normal tricuspid aortic valve, on the other hand, closes without cusp folding and therefore does not produce multiple diastolic echo sources along the lines of closure and the diastolic positions of cusp echoes is near the middle of the aortic lumen. In the case of the bicuspid aortic valve, the aortic valve diastolic position would be consistently observed near the anterior or near the posterior aortic margin depending on the location of the dominant leaflet. The eccentricity index denotes the deviation of the diastolic cusp position from the middle of the aortic lumen and takes into account the internal diameter of the aortic root. The index would equal unity if the valve cusps closed exactly in the center of the aortic root, while very high values (3.5 or above) would indicate extreme asymmetry of the cusp images. The eccentricity index was low, ranging from 1.0 to 1.25 in normal tricuspid aortic valve and high (1.5 to 5.6) in all patients with bicuspid aortic valve. The eccentricity index is 1.6 in this patient as shown in Figure 8 revealed the acquired rheumatic etiology for the bicuspid appearance in parasternal long axis view.

Pathologic SEC (spontaneous echo contrast or “smoke”) occurs when there is blood stasis due to low-flow velocity as a result of interaction between blood cells and plasma proteins, especially fibrinogen (eg. Rouleau formation) and it has been consistently associated with increased risk of thromboembolism. It is the swirling, hazy echocardiographic appearance as shown in Figure 22 and Figure 23, associated with low blood flow in mitral stenosis, atrial fibrillation and left ventricular failure. SEC usually occurs in the body of left atrium in mitral stenosis a shown in Figure 22. Atrial fibrillation in the absence of mitral stenosis is incapable of forming thrombus in the left atrial body [41] . Left atrial SEC is a better predictor of the thromboembolic risk than left atrial size [42] . Spontaneous echo contrast (SEC) is also seen in left ventricle (LV) in this patient as shown in Figure 23.

Patients with atrial fibrillation in presence of structural heart disease such as mitral stenosis as shown in ECG in Figure 1 have high embolic potential and less likely to be maintained in sinus rhythm. The atrial fibrillation, a frequent sequelae of left atrial dilation due to mitral stenosis may cause SEC in LA appendage rather than in the body of left atrium. SEC may also occur in structurally normal heart with LAA (left atrial appendage) emptying flow velocity < 55 cm/s (normal―>50 cm/s) is associated elevated risk of thrombus formation. LAA emptying flow velocity < 35 cm/s in atrial fibrillation is associated with elevated embolic risk (pulsed Doppler sample volume is placed in proximal third of appendage (mouth of appendage) in end-diastole).

Another consequence of functionally normal bicuspid aortic valve is progressive regurgitation, and it is the most common cause of pure congenital aortic regurgitation [43] . Tricuspid aortic valves with cuspal inequality are seldom incompetent in the young, but become incompetent in older patients in whom minor degrees of fibrocalcification exaggerate inherent cuspal inequality and interfere with leaflet coaptation [44] . Rarely, a severely incompetent bicuspid aortic valve becomes stenotic with virtual loss of regurgitation [45] . The echocardiographic diagnosis can be difficult in patients with heavily calcified valves [46] and identification of aortic sinuses in short axis may helpful to predict the leaflet architecture. In normal tricuspid aortic valve, the three lines of coaptation forming a “Y” (sometimes referred to as inverted Mercedes-Benz sign). In bicuspid aortic valve, the raphe can make the valve appear trileaflet during diastole, and a characteristic “fish mouth appearance” of orifice as shown in Figure 6. Rheumatic fever produces fibrotic changes, thickening and retraction of the aortic valve leaflets, resulting in central valvular regurgitation [47] as shown in Figure 10. Leaflet fusion may occur, leading to concurrent aortic stenosis as shown in Figure 15. The pathophysiology depends on whether the regurgitation is acute or chronic. In acute AR (aortic regurgitation), LV (left ventricle) does not have time to dilate in response to the volume overload, the LV end-diastolic pressure increases rapidly and causing an increase in pulmonary venous pressure leading to pulmonary edema and cardiogenic shock in severe cases. In chronic AR, the left ventricle may undergo a series of adaptive changes due to gradual increase in volume overload. LV dilation occurs as shown in Figure 9 through the addition of sarcomeres in series and as a result, the LV becomes larger and more compliant, with greater capacity to deliver a large stroke volume. Due to increased preload and the Frank- Starling mechanism, the ejection fraction (EF) is normal or even increased during early phase of chronic AR and the patient may remain asymptomatic during this period. When AR progresses, LV enlargement surpasses preload reserve and the ejection fraction falling to subnormal levels as shown in Figure 29 (LV EF―39%, the LV end-systolic volume rises and it is a sensitive indicator of progressive myocardial dysfunction. Eventually, the LV reaches its maximal diameter and diastolic pressure begins to rise, resulting in symptoms of dyspnea which may worsen during exercise.

The severity of aortic regurgitation can be assessed by Doppler studies. It is stated that the length of AR jet penetration into the left ventricle is an unsatisfactory indicator of AR severity [48] . Due to massive LV dilation, AR jet falling into the dilated LV from a height of LVOT with an appearance of “water fall” as shown in Figure 12 and it correlates with severity of regurgitation in this patient. One of the simplest and most reliable is to measure the proximal regurgitation width (height)―immediately within 1 cm below the aortic valve and compared it to LVOT diameter (left ventricular outflow tract) [49] (measured from endocardial septum to anterior mitral leaflet within 0.5 - 1 cm below the aortic valve, parallel to aortic valve plane in mid-systole) and its ratio ≥ 65% defines the severe AR and it cannot be used for eccentric jets. Figure 10 shows proximal AR jet width 20 mm and LVOT diameter 30 mm and its ratio is 66%, suggesting severe AR in this patient.

It is the smallest neck of flow region at the level of the aortic valve, immediately below the flow convergence region and the threshold of vena contracta width associated with severe AR are 0.5 cm as a highly sensitive, 0.7 cm as a highly specific and 0.6 cm as the threshold with best combination of specificity and sensitivity [50] . To approximately visualize the vena contracta, it is essential to see all the components of the regurgitant flow, i.e., the flow convergence, vena contracta and the jet. The central jet tends to expand fully in the outflow tract as shown in Figure 10 and may be inconclusive to predict the vena contracta.

The rate of deceleration of diastolic regurgitant jet and the derived pressure half-time reflect the rate of equalization of aortic and LV diastolic pressures, with increasing severity of AR. The aortic diastolic pressure decreases more rapidly. The late diastolic jet velocity is lower and hence pressure half-time is shorter [51] and a ratio <200 - 250 ms is consistent with severe AR and >500 ms with mild AR. On the other hand, pressure half-time can be lengthened or normalized with chronic LV adaptation to severe AR [52] as shown in Figure 15. In atrial fibrillation, the steeper slope of pressure decay in short cycle (PHT-194 ms) as shown in Figure 16 correlates with severity and the flat slope of pressure decay in long cycle (PHT-551 ms) as shown in Figure 15 is not correlating with severity of AR in this patient.

A brief diastolic flow reversal in aorta is normal and it is best recorded at aortic isthmus level in the upper descending aorta by pulsed-wave doppler. With increasing aortic regurgitant, both the duration and velocity of reversal increase [53] . Therefore, a holodiastolic reversal as shown in Figure 17 is usually a more specific sign of at least moderate aortic regurgitation. Retrograde flow measured by pulsed-wave Doppler immediately after subclavian artery and if end diastolic flow velocity is <18 cm/s = does not indicate hemodynamically significant AR (grade I and II), >18 cm/s = indicate hemodynamically significant AR (grade III and IV). In severe cases, the initial diastolic flow velocity is >0.6 m/s and TVI backflow signal >15 cm. In this patient, the initial diastolic flow velocity is 0.80 m/s and end diastolic velocity 0.22 m/s correlate with severe aortic regurgitation. Holodiastolic flow reversal can be used to assess the aortic regurgitation following TAVR (Transcatheter aortic valve replacement-paravalvular leak).

Among the echocardiographic parameters, the ejection fraction (EF) and end-systolic dimension are the key determinants of outcome of surgery”.

Acute insult of rheumatic fever on mitral valve leads to the formation of multiple inflammatory foci consists of Aschoff bodies, perivascular mononuclear infiltrate in the endocardium and myocardium. With time, the valve apparatus become thickened, calcified and contracted. Commissural adhesion occurs as shown in Figure 18 and ultimately resulting in mitral stenosis after a long latent period of streptococcal infection due to autoimmune mediated inflammation. Due to commissural fusion, the leaflets open with a “doming” motion as shown in Figure 9 and it results in reduction of the orifice and the conversion of the mitral leaflet-chordal apparatus from a tubular channel to a “funnel-shaped” orifice. The substantial fibrosis and calcification at the orifice of mitral valve limits inflow from left atrium to left ventricle and this limiting orifice is planimetered at the valve tips in mid-diastole as shown in Figure 20 and Figure 21, the orifice area correlate well with hemodynamic data and anatomic valve area [54] .

In general, rheumatic mitral stenosis results in a central stenotic orifice with flow directed from the center of the left atrium towards the apex of the left ventricle and collide with AR jet, producing a “bow and arrow” appearance as shown in Figure 27 and Figure 28. The differential features of etiological aspects of mitral stenosis (MS) are shown in Table 1.

It is defined as the time interval in milliseconds between the maximum mitral gradient in early diastole and the time point where the gradient is half the maximum initial value. The decline of the velocity of diastolic transmitral flow is inversely proportional to valve area (cm²) and MVA (mitral valve area) is derived by using the empirical formula (MVA = 220/T_1/2) [55] . The empirically determined constant of 220 is in fact proportional to the product of net compliance (i.e., the combined compliance of left atrium and LV) and the square root of maximum transmitral gradient in a model that does not take into account of active relaxation of LV [56] . In patients with Atrial Fibrillation, tracing should avoid mitral flow from short diastoles and average different cardiac

cycles as shown in Figure 25 and Figure 26, the mitral valve pressure half-time = 431 ms and Mitral valve area is 0.51 cm² in long cycle and 443 ms and 0.50 cm² in short cycle.

Aortic regurgitation causes the left ventricular pressure to increase more quickly in diastole than would otherwise occur. This can lead to shortening of pressure half-time and an underestimate of mitral stenosis severity. Early diastolic deceleration is prolonged when LV relaxation is impaired while it tends to be shortened in case of decreased LV compliance [57] . Rapid decrease in mitral velocity flow, i.e., short T_1/2 can be observed despite severe MS in patients who have a particular low atrial compliance [58] . The deceleration slope is sometimes bimodal, the deceleration of mitral flow velocity being more rapid in early diastole than during the following part of the E-wave and in such cases, the deceleration slope in mid-diastole rather than the early deceleration slope be traced [59] . Planimetry is considered as the reference measurement of mitral valve area (MVA) [60] . The mitral valve areas measured by pressure half-time is 0.51 cm² and 0.50 cm² as shown in Figure 25 and Figure 26 are not correlated well with planimetry measurements as shown in Figure 20 (0.98 cm²) and 0.71 cm² in Figure 21. The difference in planimetry measurements is due to positional variations, the point at which the orifice is planimetered [61] . Assessment of valve area using continuity equation and PISA (proximal isovelocity surface area) method are not recommended for routine use.

The hallmark of rheumatic heart disease (RHD) was increased echogenicity of leaflets with decreased excursion and reduced separation of the anterior and posterior leaflets. There is “paradoxical” anterior diastolic motion of the posterior mitral leaflet as shown in Figure 29, due to tethering at the tips resulted in an obligatory anterior motion of the posterior mitral leaflet tips, that due to commissural fusion, were tethered to the larger anterior leaflet.

EPSS (E-point to septal separation)-EPSS is the distance (mm) from the anterior septal endocardium to the maximal early opening point (E-point) of the mitral valve and it is the first of M-mode findings to predict systolic dysfunction, an indirect measure of a reduced ejection fraction. The normal EPSS is 6 mm and a longer EPSS (24 mm as shown in Figure 29) represent a lower ejection fraction (EF-39%). The ESD (end-systolic diameter―65.2 mm and LV dilation is 103 mm in this patient as shown in Figure 9 and Figure 29.

A patient with a low ejection fraction but a resting AS (aortic stenosis) velocity >4 m/s does not have a poor left ventricle. The ventricle is providing a normal response to high after load (severe AS), and ventricular function will improve after relief of stenosis. In this patient, a resting AS (aortic stenosis) velocity of 2.41 m/s (PG― 24 mmHg) as shown in Figure 15 with a low ejection fraction (39%) indicating that the ventricle is poorly responding to high afterload. Absence of contractile reserve (failure to increase stroke volume or ejection fraction > 20%) is a high surgical mortality and poor long-term outcome although valve replacement may improve LV function and outcome even in this subgroup [62] .

When LV systolic dysfunction co-exists with severe aortic stenosis, the AS velocity and gradient may be low despite a small valve area, a condition termed “low-flow low-gradient AS” and is characterized by effective orifice area <1 cm², LV ejection fraction <40% and a mean pressure gradient <30 - 40 mmHg.

The severity of aortic stenosis may be underestimated because decreased stroke volume due to mitral stenosis reduces the aortic gradient and may result in low cardiac output and therefore, low-flow low-gradient AS as shown in Figure 15.

In case of severe AR, the pressure half-time method for assessment of mitral stenosis is not valid. In severe AR, the left ventricle is more likely to become “full” so that the pressure half-time will be short with a poorly tolerated aortic valve insufficiency.

Severity assessment of rheumatic mitral stenosis should rely mostly on valve area (<1 cm²―severe, 1 - 1.5 cm²―moderate, >1.5 cm²―mild) and it is significant and symptomatic when MVA is <1.5 cm². It is specific, because of multiple factors influencing other supportive findings such as mean gradient (<5 mmHg―mild, 5 - 10 mmHg―moderate, >10 mmHg―severe) and systolic pulmonary artery pressure (<30 mmHg―mild, 30 - 50 mmHg―moderate, >50 mmHg―severe). However, normal resting value of pulmonary artery pressure may be observed even in severe MS. A diameter of the tricuspid annulus >40 mm seems to be more reliable than quantification of regurgitation to predict the risk of severe late TR after mitral surgery [63] . Tricuspid annulus diameter is 39.2 mm and mitral annulus diameter is 55 mm in this patient as shown in Figure 23 and reflecting no pulmonary hypertension.

The echocardiographic scoring system (Wilkins score [64] ) has been used as a valuable tool for patient selection to PMC (percutaneous mitral commissurotomy/or percutaneous balloon valvuloplasty). Impairment of mitral anatomy is expressed in scores combining different components of mitral apparatus or using an overall assessment of valve anatomy. Leaflet mobility, valvular thickening, valvular calcification, and subvalvular disease are each given a score of 0 - 4 and the total score is the sum of four items and ranges between 4 - 16. A total score of <8 results in good short and long-term outcome with balloon valvuloplasty. With higher scores (>14) indicate more severe involvement and prefer valve replacement.

In Cormier score [65] , it is grouped as Group 1 (pliable non-calcified anterior mitral leaflet with mid subvalvular disease i.e., thin chordae ≥ 10 mm long), Group II (pliable non-calcified anterior mitral leaflet and severe subvalvular disease i.e., thickened chordae < 10 mm long), Group III (calcification of mitral valve of any extent, as assessed by fluoroscopy whatever the state of subvalvular apparatus).

Echocardiographic parameters of this patient are shown in Table 2.

Since the patient is having significant LV dysfunction and improving with antifailure measures , he was advised to continue the same line of management along with oral warfarin 2.5 mg daily to maintain INR (International normalised ratio) between 2 to 3 and statin therapy (atorvastation 10 mg daily). Patient is taking penicillin prophylaxis regularly every 3 weeks and advised for life long.

Vasodilator therapy may be used to reduce after load in patients with systolic hypertension and chronic aortic regurgitation, in order to minimize wall stress and optimize LV function. However, in normotensive patients, vasodilator therapy is not likely to reduce regurgitant volume (preload) significantly and thus may not be of clinical benefit [66] . Vasodilators such as ACE (angiotensin-converting enzyme) inhibitors were not given due to intractable cough produced by these agents.

If symptoms worsens, the patient may be referred for double valve replacement (both aortic and mitral valves) with mechanical prostheses since the LVEDD (left ventricular end-diastolic diameter) is >70 mm [67] , the EF (ejection fraction) is <55%, ESD (end-systolic diameter) is >55 mm (the “55 rule” [68] ―applicable even in asymptomatic patients).

When the diameter of aortic root is >45 mm, concurrent aortic root repair or replacement is indicated and it is not warranted since the aortic root is 43.2 mm. Exclusion of coronary artery disease by angiography may be needed at the time of surgery since the age is 41 years.