Valvular Heart Disease

The four cardiac valves consist of either cusps or leaflets that close to prevent the blood from flowing backwards. When pressure behind the valve builds up, the valve opens, after blood has passed through, the pressure is reduced and the valve closes, actively or passively.

Epidemiology

Rheumatic valve disease used to be the most prevalent etiology of valvular cardiac diseases worldwide. In developing countries, rheumatic heart disease remains the most common cause of valvular heart disease. Over the past 60 years, the etiology of most valvular heart disease in industrialized countries shifted towards degenerative etiologies, mainly because of a decrease in acute rheumatic fever. However cardiac valve diseases remain common in industrialized countries, mainly because the decrease in rheumatic valve disease is compensated by an increase in degenerative valve disease, with an important contributing fact being the aging population of industrialized countries. This shift in pathologic etiology accounts for differences in patient characteristics and distribution of type of valvular lesions. [1]

In the US population, the national prevalence of moderate and severe valve disease was estimated at 2,5%, determined by echocardiography. In another cohort, prevalence based on clinical signs and symptoms, confirmed by echocardiographic imaging, the estimated prevalence of at least moderate valvular diseas was estimated at 1,8%. This difference indicates the under diagnosing of valvular heart disease, and illustrates the fact that diagnosis on the basis of clinical information alone is not reliable. [2]. Prevalence did not change according to gender, but increased substantially with advancing age, with 13,2 % after the age of 75 years, versus <2% prior to 65 years old. The predominance of degenerative etiologies accounts for the higher prevalence in the elderly. Moreover, the prevalence of degenerative valve disease is expected to rise with the aging population of Western countries.

Mitral regurgitation was found to be the most frequent valvular disease, with a prevalence of 1,7 %, followed by aortic regurgitation (0,5%), aortic stenosis (0,4%) and mitral stenosis (0,1%). Mean age of patients presenting to the hospital in the Euro heart survey was 65 years [3]. In this survey, 63% of all cases of native valve disease were of degenerative etiology. Aortic stenosis was found to be the most frequent valvular disease of patients referred for treatment. In 22% of all patients etiology was rheumatic heart disease.

In developing countries, approximately 30 milion cases of rheumatic fever occur annually, in general before the age of 20. [4]. Approximately 60% of patients will develop rheumatic heart disease, which becomes clinically evident 1 to 3 decades later [5]. Rheumatic heart disease remains the most common cause of valvular heart disease in third world countries. In western countries, rheumatic heart disease is the second most common cause of valvular heart disease.

Pathophysiology

Normal valves

All cardiac valves have similar well defined interstitial cell layers, covered by endothelium. The three cell layers have specific features, and are named fibrose, spongiosa, and the ventricularis. During the cardiac cycle, the spongiosa rich in glycosaminoglycans, facilitates the relative rearrangements of collagenous and elastic layers. Valvular interstitial cells (VIC) are abundant in all layers of the cardiac valves and comprise a diverse, dynamic population of resident cells. Regulation of collagen and other matrix components is ensured by enzymes, synthesized by VICs. Integrity of valvular tissue is maintained by interaction of valvular endothelial cells (VECs) with VICs. Changes and remodeling of valvular interstitial and endothelium cell leads to changes in properties and potentially function of the valve.

Aortic valve

The tricuspid aortic valve separates the left ventricle outflow tract from the aorta. Behind the three semilunar shaped cusps of the aortic valve are dilated pockets of the aortic root, called sinuses of Valsalva. The right coronary sinus gives rise to the right coronary artery, the left coronary sinus gives rise to the left coronary artery. The commissures are the areas where attachments of two adjacent cusps to the aorta meet.

The commissure between the left en non coronary leaflets is positioned along the area of mitro-aortic continuity. The three cusps ascend towards the commissures and descend to the basal attachment with the aorta. The aortic valve has passive valve mechanism, in contrast to the mitral valve. Opening and closure of the valve is a passive, pressure driven mechanism. Tissue of the aortic cusps is stretched via a backpressure in diastolic phase with elongation and stretching of elastin. In the systolic phase, recoil of elastin ensures relaxation and shortening of the cuspal tissue [6]. Optimal functioning of the valve requires perfect alignment of the three cusps.

Mitral Valve

The mitral valve was named after a Mitre, by Andreas Vesalius [7][8]. This active valve is located at the junction of the left atrium and left ventricle. The mitral valve apparatus contains five functional components; leaflets, annulus, chordae tendineae, papillary muscles and subajacent myocardium. The annulus is a junctional zone of discontinuous fibrous and muscular tissue portion that joins the left atrium and ventricle. The anterior leaflet spans about one third of the primary fibrous, anterior part of the annulus. Part of the mitral valve anterior leaflet is in direct fibrous continuity with the aortic valve annulus, the mitro-aortic continuity. The posterior, ventricular leaflet is attached to the posterior predominantly muscular half to two third of the annulus. The mitral valve orifice is funnel shaped due to the asymmetric leaflets.

Chordae tendinae from both the anterior and posterios papillary muscles are attached to each leaflet. The papillary muscles contract and pull the chordae tendinae during systole, which closes the two mitral valve leaflets.

The mitral valvular complex comprises the mitral valve apparatus and left atrial en ventricular myocardium, endocardium and the mitro-aortic continuity. The timed passage of blood through the valve as well as the tight closure during systole is facilitated by combined actions of the mitral valvular complex. Furthermore, the mitral valvular complex contributes to the formation of the left ventricular outflow tract and facilitates the accommodation of blood, followed by the rapid, forceful ejection through into the aortic root. [9]

Pulmonary Valve

The structure of the pulmonary valve is analogous to the aortic valve structure. The leaflets are semilunar shaped, with semilunar attachments. The pulmonary valve has no traditional annulus. Anatomically, three rings can be distinguished, superior at the sinotubular junction, at the musculoarterial junction and a third ring at the base of the sinuses. [10]

Tricuspid valve

The tricuspid valve is located at the junction between the right atrium and right ventricle. The tricuspid valve apparatus consists of 3 leaflets, chordae tendinae, anterior, posterior and often a third papillary muscle. The peripheral ends of the septal, anterosuperior and inferior or mural leaflets are referred to as commissures. The tricuspid valve has no well defined collagenous annulus. The three leaflets are attached to a fibrous elliptic shaped annulus. The direct attachment of the septal leaflet is a distinctive feature of the tricuspid valve. The prominent papillary muscles support the leaflets at the commissures.

The anterior papillary muscle provides chords to the anterior and mural leaflets, the posterior papillary muscle provides chords to the mural and septal leaflets.

Normal valve function requires structural integrity and coordinated interactions among multiple anatomic components. [11] A variety of pathophysiologic mechanisms can cause cardiac valve disease.

Valvular stenosis, defined as inhibition of forward flow secondary to obstruction caused by failure of a valve to open completely, is almost always caused by a primary cuspal abnormality and a chronic disease process.

Valvular insufficiency is defined as reverse flow caused by failure of a valve to close completely, may result from either intrinsic disease of the valve cusps or from damage to or distortion of supporting structures without primary cuspal pathology.

Rheumatic valve disease

Chronic rheumatic valve disease is characterized by chronic, progressive deforming valvular disease. Anatomic lesions combine to varying degrees fibrous, or fibrocalcific distortion of leaflets or cusps, valve commissures and chordae tendineae, with or without annular or papillary muscle deformities.

Stenosis results from fibrous leaflet and chordal thickening and commissural and chordal fusion with or without secondary calcification. Fusion of a commisure in an open position can cause regurgitation, as well as scarring induced retraction of chordae and leaflets.

Aortic valve Stenosis

Obstruction of the left ventricle outflow can occur at subvalvular level (eg hypertrophic cardiomyopathy), supravalvular level or valvular level. Aortic valve stenosis is left ventricle outflow obstruction at valvular level.

In industrialized countries, aortic stenosis is the most common lesion among patients referred for treatment of valvular disease [3]. Age-related degenerative calcified aortic stenosis is the most common cause of aortic stenosis in adults in North America and Western Europe. The second most common cause is calcification of a congenitally bicuspid aortic valve. Other rare causes of calcified aortic stenosis include Fabry disease, lupus erythematosus, Paget disease, and ochronosis with alkaptonuria. The most common etiology of aortic stenosis worldwide remains rheumatic heart disease.

Prevalence of aortic valve abnormalities increases due to age-related pathology in the ageing population. The first detectable macroscopic modifications of the calcification process is named aortic valve sclerosis. [6] Aortic sclerosis, seen as calcification or focal leaflet thickening with normal valve function, was detected in 25% of people at 65 years of age, this increases to 48% in people aged >75% in a population-based echocardiographic study. [12] [13]

The prevalence of calcified aortic stenosis is estimated at 2 % of people 65 years of age, increasing to 3-9% after the age of 80 years. [2] [12]

Calcified degenerative aortic valve stenosis was previously considered to be the result of a passive degenerative process due to longterm mechanical stress in combination with calcium accumulation. Recently this concept is revised. Calcified degenerative aortic stenosis is considered an active pathobiological process, including proliferative and inflammatory changes, lipid accumulation, renin-angiotensin system activation, valular interstitial cell transformation, ultimately resulting in calcification of the aortic valve [14][15] [16] [17]. Risk factors for development of calcific aortic stenosis are similar to those for vascular atherosclerosis such as diabetes, hypertension, and cholesterol levels. [18] [19] Progressive calcification leads to immobilization of the cusps causing stenosis.

Severity of outflow obstruction gradually increases in aortic valve stenosis. Left ventricular output is maintained by the adaptation of the increasingly hypertrophic left ventricle. This compensational mechanism serves to normalize the left ventricle wall stress. Left ventricular hypertrophy in combination with the prolonged systolic phase of the cardiac cycle results in increased myocardial oxygen demand. The mismatch between oxygen demand and supply is the main mechanism for angina pectoris in aortic stenosis.

As the stenosis progresses, the left ventricle becomes less compliant with subsequent limited preload reserve. Eventually, the left ventricle will decompensate with a decline in cardiac output and rise in pulmonary artery pressure.

Aortic stenosis is assessed by estimating the mean systolic pressure gradient and aortic valve area (AVA) Measurement of valve area is an important part of the assessment of the severity of aortic stenosis. The normal aortic valve area is 3-4 cm2. A valve area of <1 cm2 implies severe aortic stenosis The valve area may decrease by as much as 0.12 ± 0.19 cm 2 per year. [20] In late stages of severe aortic stenosis, cardiac output declines due to systolic dysfunction of the left ventricle, with a decline in the transvalvular gradient.

Clinical Presentation

Symptoms of degenerative aortic stenosis manifest with progression of the disease. The first symptoms usually commence in the seventh or eight decade. Symptoms are typically noted on exertion. Dyspnoea on exertion is the most common encountered first symptom. Other symptoms are angina, precipitated by exertion and relieved by rest, syncope and heart failure. The findings on physical examination vary with the severity of aortic stenosis. On auscultation, a systolic ejection crescendo-decrescendo murmur, radiating to the neck is audible, often accompanied by a thrill. An elevated left ventricular pressure in patients with aortic stenosis, in conjunction with mitral annulus calcifications predisposes to rupture of mitral chordae tendineae, which may produce a regurgitant systolic murmur. [21] [22]

The first heart sound is usually normal or soft in patients with aortic stenosis. The second heart sound may be delayed due to prolongation of systolic ejection time. The S 2 also may be single because of superimposed aortic and pulmonic valve components, or the aortic valve component is absent or soft because the aortic valve is too calcified and has become immobile. If the aortic component is audible, this may give rise to a paradoxical splitting of S2. A pronounced atrial contraction can give rise to a palpable and audible S4.

When stroke volume and systolic pulse pressures fall in severe aortic stenosis, a pulsus parvus (small pulse) may be present. A wide pulse pressure is also characteristic of aortic stenosis. A pulsus parvus et tardus (the arterial pulse is slow to increase and has a reduced peak) can be appreciated by palpating the carotid pulse of patients with severe aortic stenosis. The stenotic valve decreases the amplitude and delays the timing of the carotid upstroke. The rigidity of the vasculature may hamper this sign in the elderly.

Diagnostic options

Chest Radiography

In aortic stenosis, cardiac silhouette and pulmonary vascular distribution are normal unless cardiac decompensation is present. Post-stenotic dilatation of the ascending aorta is frequent. Calcification of the valve is found in almost all adults with severe aortic stenosis; however, fluoroscopy may be necessary to detect it. A late feature in patients with aortic valve stenosis is cardiomegaly. In patients with heart failure, the heart is enlarged, with congestion of pulmonary vasculature.

The right atrium and right ventricle may also be enlarged in advanced heart failure.

Electrocardiography

In approximately 85% of patients with aortic stenosis, left ventricle hypertrophy, with or without repolarization abnormalities is seen on electrocardiography (ECG). Left atrial enlargement, left axis deviation and conduction disorders are also common. Atrial fibrillation can be seen at late state and in older patients or those with hypertension.

Echocardiography

The best non-invasive diagnostic tool to confirm the diagnosis of aortic stenosis, assess the number of cusps and the annular size, is ultrasonic examination of the heart. Quantification of valvular calcification is possible. In 1998, the American college of cardiology/American Heart Association (ACC/AHA) task force [23] recommended the diagnostic use of echocardiography.

Echocardiographic imaging evaluates the severity and etiology of the primary valvular lesion, secondary lesions, and coexisting abnormalities. The size and function of the atria and ventricles can be evaluated as well as hemodynamic characteristics. Echocardiography is also performed for postprocedural evaluation of patients.

To assess the severity of aortic stenosis, transvalvular gradients and maximum jet velocity is measured using Doppler echocardiography, and aortic valve area is calculated. The systolic gradient across the stenotic aortic valve depends on stroke volume, systolic ejection period, and systolic pressure in the ascending aorta. The stenotic valve area is inversely related to the square root of the mean systolic gradient. Due to their flow-dependency these measurements are most valuable in normotensive patients.

Valve thickening and calcification, as well as reduced leaflet motion can also be assessed using Doppler.

Computed tomography

Although the role of computed tomography (CT) in clinical management is currently not well defined, This imaging modality could improve assessment of the ascending aorta. CT has an established role in evaluating the presence and severity of aortic root and ascending aortic dilatation in patients with associated aortic aneurysms. The high sensitivity and specificity of CT in detecting high-grade coronary artery stenosis could be useful to preoperatively rule out coronary artery disease.

Both electron beam and multislice cardiac CT can be useful in quantifying valve calcification, which have been shown to correlate with echocardiographic assessment and clinical outcome. Prior to transcatheter aortic valve implantations, CT provides information concerning the aortic valve area, annulus size, and the distance between the aortic cusps and the coronary ostia.

Cardiac Magnetic Resonance Imaging

Cardiac MRI (CMR) has an established role in evaluating aortic root and ascending aorta anatomy. This imaging modality can be used to measure the aortic valve area, but the role of CMR in the management of aortic stenosis is currently not well defined.

Cardiac Catheterization

Cardiac catheterization remains the gold standard to detect coronary artery disease. Currently, in patients with aortic stenosis, cardiac catheterization is most often performed to identify the presence of concomitant coronary artery disease (CAD). In patients with inconclusive noninvasive tests, hemodynamic abnormalities can be assessed by cardiac catheterization. Coronary angiography is recommended prior to aortic valve replacement.

Exercise Testing

Since aortic stenosis is a progressive disease, most common in the elderly population, many patients with aortic stenosis do not recognize gradually developing symptoms and cannot differentiate fatigue and dyspnea from aging and physical deconditioning. Lifestyle modification may mask symptoms. Although contraindicated in patients with severe aortic stenosis, Exercise testing is useful for risk stratification and eliciting symptoms. Under supervision, it is reasonable to propose exercise testing in patients >70 years who are still highly active.

Treatment

Medical treatment

For many years the standard of care for patients with significant aortic valve stenosis has been to provide antibiotic prophylaxis against infective endocarditis. However, current AHA guidelines for prevention of infective endocarditis no longer recommend antibiotic prophylaxis for this group of patients. Exceptions are patients with a prior episode of endocarditis, patients with prosthetic valves or with additional complex cardiac lesions inducing with consequently a high risk for the development of endocarditis. Patients who have had rheumatic fever should still receive antibiotic prophylaxis against recurrences of rheumatic fever.

No medical treatment has proven to delay the progression of aortic stenosis. Surgery is inevitable for symptomatic patients. Patients at prohibitive risk for intervention may benefit from medical treatment including digitalis, diuretics, ACE inhibitors, or angiotensin receptor blockers, if experiencing heart failure. Beta-blockers should be avoided in these circumstances.

Surgery

The infinitive treatment for aortic valve stenosis is aortic valve replacement.

The first cardiac valve surgery under direct vision was an aortic valve replacement, performed in 1960 by dr. Dwight Harken [24] The aortic valve was replaced by a caged ball valve, which became the standard for aortic valve replacement. [25] [26]

A total of more than 70 different mechanical aortic valve models have been introduced in aortic valve replacement and implanted in humans in the past 5 decades. The mechanical prostheses can be divided into 3 large groups: the first generation of ball valves, second generation of tilting-disc valves, and the last generation of bileaflet valves. [27]

In 1962 Donald Ross implanted the first aortic valve allograft. In 1967 he replaced a patient’s malfunctioning aortic valve with the patients own pulmonary valve. An aortic or pulmonary valve homograft was then used to replace the patient’s pulmonary valve. This procedure is known as the Ross Procedure. Currently, the Ross procedure may be considered for bicuspid aortic valve stenosis, particularly for young women of reproductive age.

Transcatheter intervention

In 2002, the first transcatheter aortic valve implantation was performed by dr. Alain Cribier. A transcatheter aortic valve implantation is a less invasive treatment option for patients at prohibitive risk for conventional aortic valve replacement. In this technique, the native valve is not excised. After balloon valvuloplasty, the prosthetic valve is implanted in the aortic position, with the frame of the prosthesis covering the native valve. The bioprosthesis can be implanted retrograde or antegrade. Currently 4 different approaches may be used in this technique (Insert table reference here). Transcatheter aortic valve implantation is assessed in randomized clinical trials and registries.

Prognosis

Aortic valve stenosis has a severe prognosis when any symptoms are present, with survival rates of only 15–50% at 5 years. Strongest predictors of poor outcome in the elderly population are high New York Heart Association (NYHA) class (III/IV), associated mitral regurgitation and left ventricular dysfunction. Survival is only 30% at 3 years with the combination of these three factors.

Bicuspid Aortic valve

Bicuspid Aortic valve disease affects as many as 1-2% of the population, and is the most frequent congenital cardiovascular malformation in humans. [28]

A bicuspid aortic valve may be part of a phenotypic continuum of congenital aortic valve disorders, associated with unicuspid valves, bicuspid valves, the normal tricuspid valves and the rare quadricuspid forms. Understanding of the pathogenesis of aortic valve malformation remains incomplete.

Bicuspid aortic valves are three to four times more common in men than in women. Bicuspid aortic valve disease results from abnormal cusp formation during valvulogenesis, but coexisting genetic abnormalities of the aorta and proximal coronary vasculature are often present. Moreover, nonvalvular findings occur in up to 50% of patients with bicuspid aortic valves. Associated findings are aortic dilation, aneurysms and dissection.

During valvulogenesis, adjacent cusps of the bicuspid valve fuse to form a single aberrant cusp. This fusion results in large leaflet, yet smaller than 2 normal cusps, with most often a central raphe or ridge. Fusion of the right coronary and noncoronary cusps is associated with cuspal pathology. Fusion of the right and left coronary cusps is associated with coarctation of the aorta.

Although endocarditis can be a devastating complication of bicuspid aortic valve disease, straightforward bicuspid aortic valve disease is no longer an indication for bacterial endocarditis prophylaxis according to the ACC/AHA practice guidelines. The risk of endocarditis is felt to be low in patients with straightforward bicuspid aortic valve disease. An exception to this recommendation is a patient with a prior history of endocarditis. [29]

Clinical Presentation

In infancy, bicuspid aortic valve disease is often asymptomatic. By adolescence an estimate 1 of 50 children born with these abnormalities will have clinically significant obstruction or regurgitation. [30]

Complications of bicuspid aortic valve disease are common in adulthood [31]. The abnormal shear stress leads to valve calcification and further aortic root dilation has been reported. [32] The most common complication is aortic stenosis, caused by premature fibrosis, stiffening, and calcium deposition. The majority of patients under 65 years of age with significant aortic valve stenosis have bicuspid aortic valve disease. A more rare complication of bicuspid aortic valve disease is aortic regurgitation. 15% of all cases of aortic regurgitation in the Euro Heart survey had bicuspid aortic valve disease. On auscultation, an ejection sound can be audible, best heard at the apex. There may be associated murmurs of aortic stenosis, incompetence, or coarctation of the aorta when these lesions are present.

Diagnostic options

Imaging

Echocardiography is used to confirm the diagnosis of bicuspid aortic valve disease. Reported sensitivities and specificities of echocardiography for detecting BAV anatomy are 92% and 96% respectively. To establish the diagnosis, visualization of the aortic in systole in the short-axis view is essential. During diastole, the raphe can make the valve appear trileaflet. In the long-axis view, the valve often has an eccentric closure line and there is doming of the leaflets. Transesophageal echocardiography may improve visualization of the leaflets in case of inconclusive visualization during transthoracic echocardiography. The thoracic aorta is visualized by alternative imaging modalities such as cardiac magnetic resonance imaging (MRI) or computer tomography (CT). Both cardiac MRI and CT images can help to confirm the bicuspid anatomy of the aortic valve.

In all patients, serial transthoracic echocardiography should be performed to evaluate the valve and disease progression. Annual cardiac imaging is recommended for patients with significant valve lesions or with aortic root diameters >40 mm. Complete imaging of the thoracic aorta should be performed periodically for surveillance. [33]

Treatment

Medical treatment

In patients with bicuspid aortic valve disease, high blood pressure should be aggressively. The ACC/AHA guidelines for the management of adult congenital heart disease and guidelines for the management of patients with valvular heart disease suggest that it is reasonable to use beta-blockers in this population (Class IIa recommendation). [34] This is in accordance with the standart of care at many centers to slow the progression in Marfan-associated aortopathy.

Surgery

Indications for surgery are similar to that in patients with “degenerative aortic valve disease”; intervention is indicated for severe valvular dysfunction, symptomatic patients, and patients with evidence of abnormal left ventricular dimensions and function.

In children and young adults, the bicuspid valve is not calcified and balloon valvuloplasty is recommended. A prosthetic valve implantation would be suboptimal due to the continuing growth of the child.

Indications for valvuloplasty in children include peak-to peak gradients >50 mm Hg with ST- or T-wave changes at rest or with exercise. Valvuloplasty is also indicated for symptomatic children with peak-to-peak gradients >60 mm Hg. [34]

Surgical options for adult bicuspic aortic valve disease include valve replacement (bioprosthetic or mechanical valves), Ross procedure or valve repair (for those with aortic incompetence) Surgical aortic valve replacement is the most common procedure in adults with bicuspid aortic valve disease, for either aortic valve stenosis or regurgitation. Indications of interventions are similar to those described for tricuspid aortic valve disease in the ACC/AHA guidelines for the management of patients with valvular heart disease. [32]

Approximately 30% of adults with bicuspid aortic valve disease undergoing aortic valve replacement will also need aortic root surgery. Surgical attention for dimensions of the aortic root is essential because of the risk of further root dilation. The ascending aorta in patients with bicuspid aortic valve disease increases 0.2 to 1.2 mm/year. [35]

Guidelines suggest that changes in root size more than 0.5 cm/year are an indication for root replacement. Aortic root dimensions of 5.0 cm require intervention and aortic root dimensions of 4.5 cm require intervention if surgery is performed for valvular indications according to current guidelines.

Prognosis

Life expectancy in adult patients with bicuspid aortic valve disease is not shortened when compared with the general population. 10-year survival in asymptomatic adults with bicuspid aortic valve disease with a spectrum of valve function, was 96% [31]. In asymptomatic adults with bicuspid aortic valve disease without significant valve dysfunction the 20-year survival was 90%. [36]

Aortic Regurgitation

A variety of aetiologies can cause aortic regurgitation by preventing proper coaptation of the aortic valve leaflets with a subsequent diastolic reflux of blood from the aorta into the left ventricle. Etiology of aortic regurgitation can be primary valvular, or it can be primarily caused by aortic root or disease.

The origin of primary valve disease may be calcific aortic disease, idiopathic degenerative disease, endocarditis, rheumatic disease, a biscuspid aortic valve, or myxomatous proliferation of valvular tissue. In the majority of patients the disease is caused by rheumatic disease. However, in Western countries the disease is most often of degenerative origin. In the Euro Heart Survey degenerative aortic regurgitation accounted for approximately half of the cases of aortic regurgitation, 15% of cases had a bicuspid aortic valve [3]. Accelerated degeneration of valve leaflets, resulting in regurgitation similar carcinoid syndrome related regurgitation, can be caused by certain anorectic medications, such as fenfluramine and phentermine [22].

Aortic annulus dilation, without primary involvement of the leaflets may result in aortic regurgitation due to leaflet separation. Aortic regurgitation of primary aortic root or annulus etiology includes idiopathic aortic root dilatation, aortic dissection, trauma, and chronic severe systemic hypertension. Aortitis representing less than 5% of the aetiologies of aortic regurgitation and may be due to inflammatory disease, such as giant cell, Takayasu and Behcet syndrome. Syphilis and ankylosing spondylitis may affect the aortic valve, but may also be associated with aortic dilatation. Other systemic arteritides and connective tissue disorders such as Marfan syndrome, Reiter disease, Ehlers-Danlos syndrome, osteogenesis imperfecta, and rheumatoid arthritis can lead to annular dilatation and valvular insufficiency. In patients without generalized tissue disease the same pattern of ascending aortic enlargement is known as annuloaortic ectasia. Chronic aortic regurgitation itself may lead to progressive aortic root dilatation.

Aortic valve regurgitation is often accompanied by other valvular abnormalities. Aortic valvular insufficiency is most commonly seen in combination with aortic stenosis.


Aortic insufficiency due to rheumatic etiology is often associated with mitral valve disease. The valve leaflets are retracted by fused commissures and fibrotic scarring of the leaflets itself.

Aortic cusp prolapse can be isolated, or due to myxomatous degeneration, sometimes with associated mitral or tricuspid valve involvement. In 15% of patients with ventricular septum defect prolapse of an aortic cusp leads to aortic insufficiency.

Isolated aortic regurgitation is often caused by a primary aortic annular etiology. Rheumatic origin is much less common in patients with pure aortic regurgitation. In approximately 10% of cases, aortic regurgitation results from infective endocarditis, with perforation or erosion of leaflets.

It is of considerable clinical importance to distinguish between acute aortic regurgitation and chronic regurgitation, since acute aortic regurgitation can be life-threatening if not treated immediately, in contrast to chronic regurgitation which can be tolerated for years.

Pathophysiology

In patients with aortic insufficiency the regurgitating volume increases total stroke volume. This volume might equal the effective forward stroke volume in patients with severe aortic regurgitation. In chronic aortic regurgitation, several compensatory mechanisms ensure cardiac output.

Acute aortic regurgitation

Acute aortic regurgitation is a sudden hemodynamically significant aortic incompetence, which can often be catastrophic. An increase in left ventricular end diastolic volume with absence of ventricular remodelling may lead to elevated left atrial and pulmonary artery wedge pressure and decreased effective cardiac output, with compensatory tachycardia to maintain sufficient output.

Acute severe aortic regurgitation typically occurs with infective endocarditis, trauma, and aortic dissection. The left ventricle cannot dilate sufficiently. The patient may present with chest pain due to increased myocardical oxygen consumption combined with decreased coronary bloodflow from changes in diastolic perfusion. Coronary bloodflow in acute aortic insufficiency occurs during stystolic cardiac phase. Other symptoms of acute aortic regurgitation are tachypnea, tachycardia and rapidly progressive pulmonary edema and/or cardiogenic shock.

Chronic Aortic regurgitation

Causes of chronic aortic regurgitation 
aortic root/annular dilation
congenital bicuspid valve
previous infective endocarditis
rheumatic
in association with other diseases

Aortic root dilatation, annular dilation and congenital bicuspid valve are, in developed countries, the most common causes of severe chronic Aorta regurgitation.

The slow process of chronic aortic regurgitation allows adaptation of the ventricle to the increased preload and afterload. The left ventricular compensates to the regurgitant flow, the increased volume and pressure by enlargement. The left ventricle end diastolic pressure remains relatively low and does not approach the aortic diastolic pressure. The additional stroke volume is responsible for increased systolic pressure and eventually the wide pulse pressure. The systolic hypertension further increases left ventricle afterload.

In contrast to the compensatory mechanism in mitral valve regurgitation, a modest concentric left ventricular hypertrophy accompanies the eccentric hypertrophy, with a normal mass-to-volume ratio(Feiring and Rumberger 1423-32). In a chronic state, progressive left ventricle dilatation leads to pre- and afterload mismatch. With gradually decompensation and deterioration of systolic function, the ventricle is not able to sustain perfusion.

Clinical presentation

Patients with aortic regurgitation typically present with symptoms of left sided heart failure including dyspnea on exertion, orthopnea, fatigue, and occasionally paroxysmal nocturnal dyspnea. Angina is less common in patients with aortic regurgitation compared to aortic stenosis. The reduced aortic diastolic blood pressure reduces the coronary blood flow, resulting in angina. The same mechanism is presumed to cause syncope.

Diagnostics

Chest Radiography

Chest Radiography in acute aortic regurgitation reveals minimal cardiac enlargement, with normal aortic root and arch. In acute aortic regurgitation, signs of left heart failure are frequent. Cardiomegaly with left ventricular enlargement is the main feature on chest radiography in chronic aorta regurgitation. The ascending aorta may be enlarged in case of an aortic aneurysm or aortic dissection but Chest X-ray is not a sensitive examination to detect ascending aortic aneurysm.

Pulmonary congestion is noted at advanced stages of chronic AR, when heart failure has developed.

Electrocardiography

Electrocardiography in patients with aortic regurgitation may be normal early in the disease. Left ventricular hypertrophy is the main feature of aortic regurgitation, with or without associated repolarization abnormalities. Left axis deviation may be present.

Echocardiography

Echocardiography is used to evaluate the anatomy of the aortic valve and other valves, as well as aortic leaflets and the aortic root. The regurgitation mechanism and aetiology can be assessed. Three types of mechanisms can be identified; enlargement of aortic root with normal cusps, cusp prolapse or fenestration and poor cusp tissue quality or quantity. Doppler is used for quantifying the aortic regurgitation by the width of regurgitant jet and its extension into the LV, the rate of decline of aortic regurgitant flow and diastolic flow reversal in the descending aorta.

Severe aortic regurgitation is defined as effective regurgitant orifice (ERO) area of >0.30cm2, regurgitant volume >60mL, or a regurgitant fraction of >50%.

Preoperatively transoesophageal echocardiography is performed to more accurately evaluate the anatomy and mechanism of the aortic valve regurgitation.

Treatment

The only direct method to reduce aortic regurgitation is surgical treatment. However, some patients may benefit from medical treatment.

Medical treatment

The relative reduction of myocardial blood due to increased demand and/or associated obstructive coronary artery disease may cause angina. Angina may be treated by reducing aortic regurgitation, reduction of myocardial demand of revascularization of the myocardium. Clinical heart failure is treated with traditional therapy, including digitalis, diuretics, and ACEI. In severe heart failure, parenteral inotropic and vasodilator therapy may be needed.

Current Guidelines 
Class I
  1. An adolescent or young adult with chronic severe AR* with onset of symptoms of angina, syncope, or dyspnea on exertion should receive aortic valve repair or replacement. (Level of Evidence: C)
  2. Asymptomatic adolescent or young adult patients with chronic severe AR* with LV systolic dysfunction (ejection fraction less than 0.50) on serial studies 1 to 3 months apart should receive aortic valve repair or replacement. (Level of Evidence: C)
  3. Asymptomatic adolescent or young adult patients with chronic severe AR* with progressive LV enlargement (end-diastolic dimension greater than 4 standard deviations above normal) should receive aortic valve repair or replacement. (Level of Evidence: C)
  4. Coronary angiography is recommended before AVR in adolescent or young adult patients with AR in whom a pulmonary autograft (Ross operation) is contemplated when the origin of the coronary arteries has not been identified by noninvasive techniques. (Level of Evidence: C)
Class IIb
  1. An asymptomatic adolescent with chronic severe AR* with moderate AS (peak LV–to–peak aortic gradient greater than 40 mm Hg at cardiac catheterization) may be considered for aortic valve repair or replacement. (Level of Evidence: C)
  2. An asymptomatic adolescent with chronic severe AR* with onset of ST depression or T-wave inversion over the left precordium on ECG at rest may be considered for aortic valve repair or replacement. (Level of Evidence: C)

Mitral Stenosis

Etiology and pathology

The leading cause of mitral stenosis is rheumatic fever, causing postrheumatic deformities. Other rare aetiologies of left atrial outflow obstruction include congenital and degenerative mitral valve stenosis, severe mitral annular and/or leaflet calcification carcinoid disease, neoplasm, left atrial thrombus, infective endocarditis with large vegetations, certain inherited metabolic disorders such as Fabry’s disease, mucopolysaccharidosis, Whipple’s disease, gout, rheumatic arthritis, lupus erythematosus, methysergide therapy, and cases related to previous implanted prosthesis or commisurotomy.

Rheumatic valvular disease causes diffuse thickening of the valve leaflets by fibrous, or fibrocalcific distortion, with fusion of one or more commisures valve commisures, and fusion and shortening of the subvalvular apparatus. This combined with increasingly rigid cusps results in narrowing of the valve. chordae tendineae, with or without annular or papillary muscle deformities.

The area of the normal mitral valve orifice is 4-6 cm2. In patients with mitral stenosis, when the valve area approaches 2 cm2 or less, an early, mid and late diastolic transvalvular gradient is present between the left atrium and ventricle. With progressive mitral stenosis, transvalvular pressure gradient increases. Mitral transvalvular flow depends on cardiac output and heart rate. Shortening of diastolic phase in increased heart rate causes symptoms by reducing forward cardiac output. Mitral stenosis develops gradually, and may be asymptomatic for years.

Clinical presentation

Patients with mitral stenosis may be asymptomatic for years. Mean age of presentation of symptoms is fifty to sixty years old. The presenting symptom in patients with mild mitral stenosis is typically dyspnea precipitated by stress or atrial fibrillation. Progression of disease with increasing left atrial and pulmonary venous pressures will cause progressive symptoms of dyspnea.

Mitral regurgitation

Mitral valve regurgitation results from inadequate mitral leaflet coaptation during systole. This allows the systolic regurgitation of blood from the high-pressure LV to the normally low-pressure LA. The regurgitating volume depends on both the size of the regurgitant orifice and the pressure gradient between the left ventricle and the left atrium. In primary mitral regurgitation, inadequate mitral leaflet coaptation results from an abnormality in any of the functional components of the mitral apparatus. Secondary or functional mitral regurgitation results from left ventricle disease and remodeling.

During systole, combined papillary muscle contraction and contraction of the dynamic annulus promote leaflet coaptation. Calcification of the annulus may hinder the sphincter-like contraction of the annulus allowing regurgitation. Secondary mitral regurgitation may be due to annulus dilation, caused by ischemic or dilated cardiomyopathy. The regurgitant volume causes left ventricular enlargement and contractile dysfunction. Left ventricle dilation may enlarge the mitral annulus and the regurgitant orifice, increasing the mitral regurgitation. Positive inotropes, diuretics and vasodilators reduce the size of the left ventricle and the regurgitant orifice, and decreases the the regurgitant flow.

Etiology

Three different types of primary mitral regurgitation can be defined; leaflet retraction from fibrosis and calcification, annular dilatation and chordal abnormalities (including rupture, elongation, or shortening). Functional mitral regurgitation results from LV dysfunction with or without annular dilation. Mitral regurgitation was classified by Carpentier into three types based on leaflet and chordal motion: normal leaflet motion (type I), leaflet prolapse or excessive motion (type II), and restricted leaflet motion (type III). [37]

Chronic mitral valve regurgitation

Degenerative mitral valve disease is the most common cause of mitral regurgitation in Europe. Myxomatous mitral valve degeneration is also known as floppy mitral valve or mitral valve prolapse. Prolapse is defined as excursion of one or both leaflets above the plane of the annulus during systole. [38] Prolapse of the middle portion of the posterior leaflet is the most common finding in degenerative MR. [39].

Mitral regurgitation in Barlow syndrome or parachute mitral valve is due to annular dilatation and extensive hooding of leaflets with large amounts of excessive leaflet tissue. In mitral regurgitation, the mass-to-volume ratio of the enlarged, thin walled left ventricle is less than 1 [40].

Clinical Presentation

Patients with mild to moderate compensated chronic mitral regurgitation may remain asymptomatic for many years. The adapted left ventricle maintains normal forward cardiac output. The left ventricle ejection fraction in chronic mitral regurgitation may be greater than normal due to the compensatory cardiac adaptations. Progression of severity depends on etiology of regurgitation; in patients with connective tissue disease regurgitation tends to progress more rapidly than patients with mitral valve prolapse or rheumatic mitral regurgitation. Progression in acute rheumatic fever is often rapid. Acute progression may by caused by endocarditis or chordae rupture.

Gradual progression and eventually decompensation results in decreased cardiac output with physical activity and pulmonary congestion. Patients present with weakness, fatigue, palpitations, dyspnea on exertion. Hepatomegaly, peripheral edema and ascites due to right sided heart failure can be associated with rapid clinical deterioration.

Acute mitral regurgitation is associated with sudden pulmonary congestion and edema. On physical examination the apical impulse is displaced laterally, indicating left ventricular enlargement. S1 is normal or diminished. S2 may be single, closely split, normally split, or even widely split as a consequence of the reduced resistance to LV ejection. A widely split S2 is often audible, due to shortening of LV systole and early closure of the aortic valve. The P2 component of the second heart sound may be increased if pulmonary hypertension has developed. The apical systolic murmur is typically holosystolic and radiates to the axilla, depending on the direction of the regurgitant jet. It can be blowing, moderately harsh, or even soft. An S3 gallop often is present, reflecting the transmitral diastolic flow during the rapid filling phase.

Early in the disease process of patients with Barlow syndrome, a characteristic midsystolic click can be appreciated, followed by a late systolic murmur; with disease progression the murmur becomes holosystolic, and the midsystolic click may become inaudible. [37]

Acute mitral regurgitation

Immediate intervention is often necessary in acute mitral regurgitation. Etiology can be organic or functional. Organic causes includes rupture of a major chorda tendinea (in myxomatous mitral valve disease) or papillary muscle (due to myocardial infarction), leaflet perforation (of endocarditic origin), and dysfunction of a prosthetic valve due to endocarditis or paravalvular regurgitation. Regurgitation of functional etiology results from left ventricular abnormalities such as dyskinetic wall due to ischemia or dilated ventricle due to cardiomyopathy.


Acute mitral regurgitation is associated with dyspnea and orthopnea, caused by sudden pulmonary congestion and edema. Acute papillary muscle rupture may mimic the presentation of a patient with a postinfarction ventricular septal defect.(Harrison et al. 697-701) On physical examination no signs of cardiac compensatory mechanisms are present. The increase in left atrial pressure diminishes the pressure gradient between the left ventricle and left atrium by midsystole. The murmur of mitral regurgitation is shortened and of decreased intensity, it may be soft, short of even inaudible. an S3 gallop usually is present. The volume overload is increasing the severity of MR over time leads to a greater percentage of the LV stroke volume being ejected in a retrograde fashion.

Diagnostic Options

Treatment

Surgical

The hemodynamic overload on the heart caused by mitral regurgitation can ultimately only be corrected by surgically restoring valve competence. For all valve surgery timing of surgery is essential. Irreversible left ventricular dysfunction will result in suboptimal results of delayed surgery. Due to the operative risk and risk of valve prosthesis surgery should however be delayed as long as possible.

Mitral valve regurgitation is surgically corrected by mitral valve replacement or repair. Mitral valve repair is generally found to be superior to replacement, with preservation of left ventricular function and part of the mitral valve apparatus.[41] [42] [43] [44] and without the use of a prosthesis. In mitral valve regurgitation indication for valve surgery is affected by symptomatic status, ventricular functional status, and the procedure to be performed. Repair might be considered in asymptomatic patients with normal left ventricular function or patients with severe impairment of left ventricular function who might not be candidates for mitral valve replacement.

For most patients, mitral valve surgery is performed for the relief of symptoms or to prevent worsening of asymptomatic left ventricular dysfunction.

Tricuspid stenosis

Tricuspid stenosis (TS) is most commonly of rheumatic origin. The anatomical characteristics are similar to those of mitral stenosis including fibrous leaflet thickening and fusion and shortening of the subvalvular apparatus. The preponderance of cases are in young women. Other etiologies of right atrial obstructiuon are rare and include congenital tricuspid atresia right atrial tumors and carcinoid syndrome.

Clinical presentation

The reduced cardiac output in tricuspid valve stenosis causes symptoms of fatigue and malaise. On physical examination right upper quadrant tenderness with a palpable liver with a presystolic pulse may be noted. Significant peripheral edema and ascites can develop. A tricuspid opening snap and a characteristic murmur may be audible on auscultation at the left sternal border.

Diagnostic Options

Chest radiography

Cardiomegaly with increased the right atria and pulmonary artery size may be demonstrated on chest x-ray.

Echocardiography

Echocardiographyi is used to evaluate the valvular anatomy. It can reveal thickened tricuspid valve leaflets, reduced leaflet mobility, and a reduced orifice of flow.

Treatment

Tricuspid balloon valvotomy can be used to treat tricuspid stenosis; however, there is the potential for inducing severe tricuspid regurgitation.

Tricuspid insufficiency

Functional tricuspid regurgitation results from distortion of the architecture and coordinated actions of the tricuspid leaflets, annulus, chords, papillary muscles, and right ventricular (RV) wall. This distortion is most commonly caused by right ventricular dilation and dysfunction from left sided heart disease with pressure/volume overload conditions. The tricuspid annulus enlarges and the shaddle shape becomes more circular. The normal annular excursion can be reduced by 50% in severe TR. [45] Functional tricuspid regurgitation is a marker of poor prognosis in patients with left ventricular cardiomyopathy. Pure tricuspid regurgitation may result from rheumatic fever, infective endocarditis, carcinoid causes, rheumatoid arthritis, radiation therapy, anorectic drugs, trauma, Marfan’s syndrome, tricuspid valve prolapse, papillary muscle dysfunction, or congenital disorders.

Clinical presentation

A reduction in cardiac output related to tricuspid regurgitation, may cause symptoms of fatigue and weakness. Right-sided heart failure may cause ascites, congestive hepatosplenomegaly, pulsatile liver, pleural effusions, and peripheral edema.

With progression of the disease, patients become cachexic, cyanotic and jaundice may be present. A parasternal pansytolic murmur increasing on inspiration may be appreciated on auscultation(Carvallo’s sign). An S3, increasing with inspiration and decreasing with a Valsalva maneuve may be audible, as well as an increased P2 if pulmonary hypertension has developed.

Diagnostic options

Chest Radiography

Cardiomegaly, increased right atrial and ventricular size and a prominent azygous vein can be demonstrated on chest x-ray. Chest Radiography may reveal pleural effusion, and ascites by upward diaphragmatic displacement.

Echocardiography

The tricuspid valve structure and function can be assessed echocardiographically, as well as the annular size. This imaging modality is used to evaluate the degree of regurgitation, pressures and ventricular function.

Cardiac catheterization

Increased right atrial and right ventricular end-diastolic pressures and the degree of pulmonary artery hypertension is documented. Pulmonary artery pressures of over 60 mm Hg usually are due to left-sided lesions leading to secondary TR.

Treatment

Treatment strategy for tricuspid regurgitation is dictated by the etiology and the underlying cause of the valve disease and the overall condition of the patient.

Medical

When pulmonary hypertension is the underlying cause of tricuspid annular dilation, medical management alone may minimize the need for surgical intervention.

Surgical

Surgical options for tricuspid regurgitation include annuloplasty or valve replacement with a mechanical valve or bioprosthesis.

Prognosis

Heart enlargement, increased pulmonary vascular mark-ings and dilated central pulmonary arteries.

Pulmonary valve stenosis

Etiology and pathology

The typical domeshaped pulmonary valve stenosis is the most common form of right ventricular outflow tract obstruction. Stenosis is caused by fusion of the pulmonary valve leafl ets and a narrowed central orifi ce. The valve is usually mobile and associated with medial abnormalities and dilation of the pulmonary trunk. PVS may be associated with Noonan, Williams, Alagille, Keutel or rubella syndromes. (Evidence-based cardiology CHAPTER 63 Adult congenital heart disease)

Clinical presentation

Most patients with mild to moderate pulmonary valve stenosis are asymptomatic. Severe pulmonary valve stenosis may cause exertional dyspnea and fatigue, chest pain, palpitations and syncope.

On physical examination, thrill along the left sternal edge, and a long systolic ejection murmur with late peak may be appreciated. S2 may be widely split with reduced or absent P2.

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