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 (See [table reference]). 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. [23]

Complications of bicuspid aortic valve disease are common in adulthood [30]. The abnormal shear stress leads to valve calcification and further aortic root dilation has been reported. [31] 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. [32]

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). [33] 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. [33]

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. [31]