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Valvular heart disease

The heart is a central pump that is responsible for circulating blood throughout the entire body. There are four chambers within the muscular structure that are responsible for carrying out this task. Owing to the fact that there are two parallel circuits for blood to flow – one carrying oxygenated blood, and the other carrying deoxygenated blood – it is important to keep the circuits in isolation. The heart valves are important structures that promote the unidirectional flow of blood through the heart. They are fibrocartilaginous structures encased in endocardial tissue that function as gates between each atrium (upper cardiac chamber) and its ipsilateral ventricle (lower cardiac chamber). 

Unfortunately, there is a wide range of disorders that can affect the heart valves. Valvular heart disease is associated with high morbidity and mortality across the world. It may be the result of an underlying cardiac disorder (e.g. valvular incompetence secondary to hypertensive heart disease) or it may be the primary site of a pathological series of events (e.g. stenotic valves in rheumatic heart disease). This article aims to review several types of valvular heart disease. The discussions will focus on the pathogenesis and pathophysiology underlying the disorders. Please review the articles on the cardiac cycle and heart valves in order to better understand valvular heart disease. 

Key facts about the valvular heart disease
Congenital valve disease Present at birth
Atresias are most common
- Tricuspid atresia
- Ebstein anomaly
- Aortic  atresia
- Pulmonary stenosis
Acquired valve disease Insult to the heart valves following another illness
May occur at any time after birth
Valvular insufficiency Valves do not close properly. Also called incompetent, regurgitant, or prolapsed valvular heart disease. 
Valvular stenosis Valves do not open properly. 

An important part of understanding valvular heart disease is grasping the concept of murmurs. Under normal circumstances, the only sounds generated by the heart valves occur when they close (i.e. the ‘lub-dub’ sounds). If the valves are not adequately closed (insufficient) or are not sufficiently opened (stenosis) then the flow of blood across the abnormal valve will generate sounds. These are called cardiac murmurs. Murmurs vary in intensity (graded 1 [only heard by a specialist using high definition stethoscopes] to 6 [easily heard without a stethoscope]), with the phase of the cardiac cycle, and with the phase of respiration. The intensity of the murmur is determined by the severity of the valve defect. They are often the first clue that a clinician may detect of underlying valvular pathology. Murmurs will also be discussed in brief within their respective sections.

Summary of the heart valves

There are four heart valves located within the heart – with two valves on either side – that can be classified into two types; atrioventricular and semilunar valves.

Heart valves (diagram)

One class of valves regulate the flow of blood from the atrium to the ventricle. These are known as atrioventricular valves and there is one on each side of the heart. On the left-hand side there is the mitral valve and on the right-hand side, there is the tricuspid valve. The other subtype of heart valves prevents blood from flowing backward from the outflow vessels (i.e. vessels that take blood away from the heart; namely the aorta from the left side of the heart and the pulmonary artery from the right side of the heart) into the respective ventricles. These valves are called the semilunar valves due to their crescentic appearance. On the left-hand side is the aortic valve, while on the right-hand side there is the pulmonary valve.

Recommended video: Heart valves
Overview of the heart valves and related structures.

The sound generated by the closure of the valve can be appreciated during auscultation of the precordial area (the part of the anterior chest wall immediately anterior to the heart). Since the atrioventricular valves close first, they generate the first heart sound (S1). The semilunar valves close after the atrioventricular valves and as such, they generate the second heart sound (S2). There is a slight delay between the closure of the aortic and pulmonary valves; with the latter closing first. Therefore, the second heart sound can be appreciated as two separate impressions (i.e. A2 – for closure of the aortic valve; P2 – for closure of the pulmonary valve).

To test your knowledge about heart valves, tackle the following quiz.

Disorders affecting the cardiac valves

There are individuals born with valvular abnormalities (congenital valvulopathies), while there are those who acquire valvular disorders at one stage or another in their life (age-related degeneration, post-inflammatory changes, or from an infectious process). Irrespective of the etiology of valvular heart disease, patients inevitably may suffer from the consequences of decreased cardiac output (such as suboptimal perfusion of vital organs and fluid overload).

However, the specific clinical complication that each patient experiences depend on the nature of the pathology as well as the valves that are involved in the pathological processes. For example, a stiff mitral valve can result in pulmonary hypertension, whereas an incompetent tricuspid valve can cause portal venous congestion. Nevertheless, there is a high risk of morbidity and mortality associated with valvular heart disease if it remains untreated.

Heart valves in a cadaver: Notice three of the four heart valves and how the cardiac vessels are related to them. (LMCA: Left main coronary artery, LCx: Left circumflex artery, RCA: Right coronary artery)

Congenital valve defects

The development of the heart valves is dependent on the formation and maturation of the endocardial cushions. There are series of biochemical processes that transform the specialized extracellular matrix in areas of the atrioventricular canal and the outflow tract of the heart. Unfortunately, the process of genetic replication is susceptible to error either randomly or as a result of interference from external factors (i.e. teratogens). 

The most commonly encountered congenital valve defects are atresias. The word is an amalgam of English prefix and Greek suffix that combine to mean “without perforation”. In the case of atretic valves, there is either an absent or suboptimal opening where the valvular orifice should be. The clinical presentation of the patient is dependent on the valve that is affected.

Tricuspid atresia 

In the case of tricuspid atresia, the orifice of the tricuspid valve is completely occluded. The pathogenesis is such that there is an unequal division of the atrioventricular canal where the left atrioventricular valve is significantly larger than the right atrioventricular valve. Coincidentally, this also means that the right ventricle is also significantly underdeveloped (i.e. hypoplastic) along with the tricuspid valve.

Because of the nature of the defect, there is significant shunting of blood from the right side of the heart to the left side. This causes mixing of oxygenated and deoxygenated blood. Inadvertently, the blood that leaves the heart to the peripheral tissue has a low oxygen concentration. Neonates with this defect are markedly cyanosed; regrettably, the disorder carries a high mortality rate early in life. 

Ebstein anomaly

The Ebstein anomaly was first described by Wilhelm Ebstein in 1866 but the term was not coined until 1927 by Alfred Arnstein. It is a congenital disorder of the tricuspid valve characterized grossly by:

  • Apical displacement of the posterior and septal tricuspid valve leaflets
  • Diverse deformity and displacement of the anterior leaflet
  • Atrialization of the right ventricle

The majority of  etiological factors resulting in this valvulopathy are related to teratogen exposure in the first trimester of pregnancy. Some of these chemicals include lithium, benzodiazepines, and varnish. While the exact genetic pathways have not yet been identified, a history of previous spontaneous first-trimester pregnancy losses is suggestive of an underlying genetic abnormality. There is a preponderance of this particular form of tricuspid insufficiency among individuals of Caucasian descent. It often occurs in association with other valvulopathies, intracardiac shunts, and accessory electrical pathways (e.g. Wolff-Parkinson-White syndrome). 

The change in the position of the cusps renders the valve incompetent, as it is no longer able to prevent blood from flowing back into the right atrium. Furthermore, although part of the right ventricle is incorporated into the right atrium, this segment of the myocardium still contracts with the rest of the right ventricle. Therefore, as the rest of the right atrium contracts, that part of the right ventricle relaxes. This creates an area where blood can become stagnant and clots may form. Also, the atrialized portion of the right ventricle contracts while the right atrium is relaxed, which further accentuates the regurgitation into the right atrium. 

The disorder may be uncovered at any stage in life – from incidental discovery during intrauterine life to adulthood. The common chief complaints associated with Ebstein anomaly are cyanosis (blue discoloration of the mucous membranes due to poor oxygen saturation), peripheral edema and ascites (associated with right heart failure), fatigue, palpitations, and sudden cardiac death. There is also a risk of developing infective endocarditis, brain abscesses, cerebrovascular accidents, and transient ischemic attacks. 

Aortic atresia 

Patients with congenitally stenotic or atretic aortic valves usually have an associated hypoplastic left ventricle. However, the exact clinical manifestation is dependent on whether the lesion is above the valve (supravalvular), below the valve (subvalvular) or affecting the valves directly (valvular). Patients with valvular aortic stenosis require a patent ductus arteriosus to facilitate perfusion of the myocardium. 

Pulmonary stenosis and atresia 

Pulmonary atresia exists on a spectrum of mild disease to the overt absence of the pulmonary valve orifice. The lesion may either exist on its own (i.e. isolated disorder) or as part of a syndrome (e.g. tetralogy of Fallot). The ventricular filling will occur as normal, however, when the ventricle contracts, the blood will be pushed against a non-compliant valve.

Consequently, the right ventricle may become hypertrophied as part of the pathophysiological process. Additionally, if the valve is partially patent, blood will be pushed at high velocity through the opening, damaging the pulmonary artery distal to the lesion (i.e. post-stenotic dilatation). In a heart with a completely atretic pulmonary valve, there is no communication between the right ventricle and the lungs. Blood is able to gain access to the lung by way of a patent ductus arteriosus. Intervention is required to maintain patency of the ductus in order for this lesion to be compatible with life. 

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Valvular insufficiency

Valves are designed to snap shut when blood attempts to flow in the opposite direction. There are intrinsic mechanisms in place to prevent the valve from inverting under extreme pressure. The chordae tendineae are attached to the rough zone of the atrioventricular valves by one end and to the papillary muscles at the other end. When the ventricles contract, the papillary muscles also contract; preventing the valve from turning inside-out under the extreme forces generated by the ventricular contraction. Additionally, the cusps of the valve are at fixed points from each other, therefore they readily occlude the valve orifice once they come together. 

It is reasonable to conclude that any disorder that will cause the cusps to move further away from each other, disrupt the papillary muscles, or disrupt the complementary patterns of opposing cusps can result in valvular insufficiency. The words prolapse, incompetent, and regurgitant are often used interchangeably when describing valvular insufficiency. Essentially, an underlying pathological process (either directly or indirectly linked to the valve) has disrupted the complementary activity of the valve. It is more commonly encountered as an acquired valvular disorder and can affect all four valves.  

Mitral regurgitation

Mitral regurgitation (also called mitral valve prolapse or mitral insufficiency) is primarily a degenerative process that results in the ballooning of one or both of the valve cusps into the left atrium during ventricular systole. It is more commonly encountered in females than in males (roughly 7:1) and affects around 3% of adults.

While an exact etiology of the disorder is not fully understood, there is a prevalence of the disorder among individuals with Ehlers-Danlos syndrome (a hereditary, diverse group of illnesses associated with decreased tenacity of connective tissues) and Marfan syndrome (also a hereditary connective tissue disorder). Mitral insufficiency in the setting of these and other genetic disorders (e.g. Loeys-Dietz syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, and others) is known as syndromic or secondary mitral insufficiency. These disorders will result in structural changes of the valve cusps that result in valvular incompetence. 

There are other disorders that can affect the cusps supporting structures, which may also cause the valve to become regurgitant. These primary or non-syndromic disorders include, but are not limited to:

  • Any condition resulting in left ventricular hypertrophy (hypertensive heart disease, hypertrophic cardiomyopathy, etc.) can result in dilatation of the mitral valve annulus. Additionally, it is possible for the supporting structures (chordae tendineae) to be stretched or ruptured and therefore non-functional. Consequently, the distance between opposing cusps will be too great for them to effectively occlude the valve orifice. Inevitably blood will reflux into the left atrium during systole. 
  • A myocardial infarction can result in death and rupture of supporting papillary muscles based on the territory that was affected. Should this phenomenon affect the papillary muscles attached (indirectly) to the mitral valve, the muscles would no longer be able to keep the valves taught during ventricular contraction. As a result, the valve would become incompetent.
  • The cusps can undergo myxomatous degeneration where there is excess deposition of mucoid substances into the histological middle layer of the valve cusps (i.e. the spongiosa layer). In addition to the hypertrophy of the spongiosa layer, there is also a reduction in the fibrosa layer (most inferior of the three histological layers). The other layer of the atrioventricular valves is the atrialis layer, which is most cranial in position. Loss of the fibrosa layer results in a decline in the durability of the valve, making it more vulnerable to the forces exerted during systole.  

The primary insults that resulted in the valvular prolapse are compounded by secondary changes incurred during each cardiac cycle. The friction generated by the valves rubbing against each other as they prolapse and return to the neutral position result in fibrous thickening. Furthermore, the leaflets also rub against the endocardial surface of the left atrium, ventricle, or both causing mural thickening. They hypermobile chords snap back and forth, hitting the endocardium of the left ventricle, resulting in a linear pattern of fibrosis along the walls. Structural changes of the leaflets provide an area for blood to settle and form thrombi. This is a set up for very serious complications of valvular heart disease including systemic infarction from vegetative emboli (e.g. stroke) and infective endocarditis.

While most patients are asymptomatic of the mitral regurgitation, there are a select few who present due to several symptoms. Some patients experience autonomic dysfunction as a result of the underlying valvular prolapse. These symptoms vary from palpitations, anxiety, and exercise intolerance to atypical chest pain, syncopal episodes, arrhythmias, and orthostatic hypotension. The exact link between the autonomic dysfunction and the mitral insufficiency is not fully understood. Other patients may present as a result of worsening valvular disease. They typically present with features of congestive heart failure such as dyspnea (difficulty breathing), orthopnea (dyspnea on lying flat), arrhythmias and palpitations, and paroxysmal nocturnal dyspnea (shortness of breath at night). 

Patients with syndromic mitral insufficiency may have distinct clinical features on inspection during the examination process. They generally appear feeble, with a low body mass index. Some individuals may have thoracic abnormalities such as kyphosis, scoliosis, pectus excavatum, or straight-back syndrome (loss of the natural thoracic kyphosis). Other pathognomonic features  for associated syndromes (e.g. the hypermobile joints of the connective tissue diseases) may also be appreciated. However, most individuals are diagnosed based on the discovery of a murmur on auscultation. The classic murmur of mitral regurgitation is best heard at the cardiac apex (most inferior and lateral palpable impulse on the anterior chest wall). The murmur is high-pitched (i.e. heard best with the diaphragm of the stethoscope) and occurs in the mid-to-late systolic phase (i.e. during or towards the end of ventricular contraction). Sometimes there is also a mid-systolic click generated by the snapping of the leaflets as they prolapse into the left atrium. Echocardiography helps to confirm the presence and severity of the prolapse. 

Note that while the normal location for the cardiac apex is at the left fifth intercostal space along the midclavicular line, the apex beat may be displaced in cases of left ventricular hypertrophy or dextrocardia (a rare phenomenon where the heart is on the right side of the thorax). So locate the apex beat prior to auscultating. 

Tricuspid regurgitation

As is the case with mitral insufficiency, tricuspid valve incompetence results in backflow of blood from the right ventricle to the right atrium during systole. It is a structural disorder related to either the leaflets of the valve, the supporting annulus, or the chordae tendineae and papillary muscles. There are no apparent racial or gender preference regarding the prevalence of this disorder. It is relatively rare, occurring in less than 1% of individuals worldwide. In addition to the Ebstein anomaly, tricuspid regurgitation is also associated with genetic disorders such as osteogenesis imperfecta, Marfan and Ehlers-Danlos syndromes. However, there are numerous acquired causes of tricuspid insufficiency. 

In most cases where the tricuspid leaflets are normal, the cause of the valvular insufficiency is due to a dilated annulus. Any disorder that may cause right ventricular hypertrophy and failure can result in dilatation of the tricuspid annulus. Under normal physiological circumstances, the pressure generated by the right ventricle is significantly lower than those in the left ventricle. That is because the resistance to blood flow in the pulmonary circulation is much less than that encountered in the systemic circulation. If there is increased resistance leading to or in the pulmonary circulation (e.g. pulmonic regurgitation and stenosis, pulmonary hypertension, mitral stenosis; all discussed below), then the right ventricle will increase its activity to overcome the resistance. Like any other type of muscle, the myocardiocytes will hypertrophy in order to generate more force to overcome the resistance. The increase in the size of the right ventricle distorts the tricuspid annulus, thus pulling the leaflets further away from each other. Additionally, the dilatation may stretch the chordae tendineae and render them useless as well. 

Tricuspid valve in a cadaver: You can easily observe the tricuspid valve by dissecting the right atrium, as shown here. The valve has three cusps (anterior, septal, posterior)

Drugs that act on serotonergic pathways (i.e. acting on serotonin receptors) have been shown to precipitate systemic reactions akin to that seen in carcinoid syndrome (which is characterized by diarrhea, bronchial constriction, dermatitis, and cutaneous flushing). Examples of these drugs include methysergide (used to treat migraine headaches), pergolide (utilized in the treatment of Parkinson disease), and fenfluramine (used to assist in weight loss). Additionally, carcinoid tumors – which are indolent, neuroendocrine tumors of the gastrointestinal tract and lungs – also release serotonergic chemicals which may also result in carcinoid syndrome.

The right side of the heart is more classically affected by drugs and gastrointestinal carcinoid tumors. The drugs are metabolized by the liver and enter the portosystemic circulation, which enters the right side of the heart via the inferior vena cava. Similarly, serotonergic compounds released from the gastrointestinal carcinoid tumor will enter the portosystemic circulation and subsequently the right side of the heart via the same route. Fortunately, most of these mediators are metabolized by the lungs; thus preventing further damage to the left side of the heart. However, in the setting of a primary pulmonary carcinoid tumor, or in the presence of a septal defect, the left heart can be exposed to high concentrations of serotonergic material before they are metabolized. Although the mechanism is unknown, the serotonergic compound causes white, plaque-like lesions composed of scanty collagen fibers and smooth muscle cells (encased in a mucopolysaccharide-based medium) to develop on the intimal surface of the leaflets and mural endocardium. The plaques cause the valve leaflets to become adherent to the adjacent walls. Regrettably, this prevents the leaflets from coming together to occlude the valve orifice during ventricular contraction.

Other pathologies that can result in mitral regurgitation (rupture of papillary muscle following a myocardial infarction, post rheumatic heart disease, post-infective endocarditis) can also cause tricuspid valve insufficiency as well. 

Left ventricular failure can result in right ventricular dilatation and subsequent failure. It is therefore not uncommon for patients with tricuspid insufficiency to present with left heart failure symptoms. Additional symptoms such as fluid retention (swelling) in the lower limbs, coughing, increased abdominal girth, exercise intolerance, and exertional dyspnea (shortness of breath with variable activity) may also be present. 

Examination of the peripheries (after obtaining informed consent) will reveal a reduced pulse volume due to the decline in the volume of blood that is pumped through the lungs and into the left side of the heart. The pulses may also be irregularly-irregular due to underlying atrial fibrillation, which may also result in tricuspid insufficiency. The patient may also show signs of significant weight loss (cachexia) due to associated changes in the neurohormonal pathways and gastrointestinal tract in response to long-standing cardiac injury. The patient may also appear jaundice, which is related to the hepatic congestion resulting from the regurgitant flow. An enlarged and pulsatile liver may also be appreciated for the same reason. Also, during the abdominal examination, excess free fluid in the peritoneum – called ascites – may also be detected. 

While palpating the precordium, a right ventricular heave is often detectable as a result of hypertrophy of that muscle mass. The jugular venous pressure is also elevated because of the backflow of blood into the right atrium and consequently the superior vena cava. On auscultation, the third and fourth heart sounds may be heard. The third heart sound is present because there is an increase in the volume of blood in the right atrium as a result of the regurgitant flow. Additionally, the third heart sound is a pathological feature of left ventricular failure, which is a known predisposing factor of tricuspid insufficiency. The fourth heart sound is present under the premise that the right atrium is pumping an increased volume of blood against a hypertrophied (i.e. non-compliant) right ventricle. The murmur of tricuspid regurgitation is a high pitched sound that is heard best with the diaphragm. It occurs throughout the entire systolic phase of the cardiac cycle; hence the term pansystolic murmur. The murmur increases with inspiration and is best appreciated at the lower left sternal edge (around the fourth intercostal space). 

Aortic regurgitation

Aortic regurgitation is a progressive disorder in which blood flows from the aorta back into the left ventricle during ventricular diastole. The mechanism of dysfunction is very similar to those discussed in mitral and tricuspid regurgitation. While most developed countries will observe valvular degeneration and congenital abnormalities as their main etiological factor behind aortic insufficiency, rheumatic heart disease is the most common cause of the disease globally. There is a wide range of prevalence of aortic insufficiency (roughly 2 – 30%), but only a minority of these individuals have severe disease. Male patients are more commonly diagnosed with aortic regurgitation than female patients. Aortic regurgitation may occur in the acute setting or over a prolonged period of time. 

The underlying pathophysiology in acute aortic regurgitation is such that there is a marked elevation in left ventricular blood volume during diastole. Additionally, there isn’t enough time available for the ventricle to expand and accommodate this increased volume. The left ventricular pressure at the end of the diastolic phase is dramatically increased over a short period of time. Consequently, the left atrial pressure, and by extension, the pulmonary venous pressure is significantly increased. The patients will begin to experience symptoms of left ventricular failure and pulmonary edema. Furthermore, the change in pressure dynamics also distorts the blood flow through the coronary vessels. This impaired myocardial perfusion on the background of increased myocardial workload creates the perfect environment for an ischemic event (i.e. a heart attack). Acute aortic valve insufficiency may be preceded by infective endocarditis, chest trauma, or iatrogenic injury during valve replacement surgery, or from an acute ascending aortic dissection. In infective endocarditis, the vegetative deposits on the valve leaflets can impede adequate valve closure, resulting in regurgitation. Chest trauma, iatrogenic injury, and aortic dissection may cause lacerations (tears) in the ascending aorta that may alter the relationship of the valve cusps; making closure impossible and regurgitation inevitable. The symptomatology of these patients manifest rapidly and includes severe shortness of breath, chest pain (in the setting of impaired coronary circulation), and heart failure. There is typically little time to act and the clinical degree of suspicion for this diagnosis should be relatively high in the presence of these symptoms. 

While the most common cause of chronic aortic regurgitation is a congenital bicuspid aortic valve, there are other acquired causes that are also quite prevalent (especially in developing countries). Rheumatic fever and its major complication of rheumatic heart disease is becoming less common in developed nations but still accounts for a significant amount of cases of aortic regurgitation. The disorder is preceded by a bacterial infection (group A streptococcus) and subsequent molecular mimicry leading to an autoinflammatory response. The inflammatory response promotes fibrosis and hypertrophy of the aortic leaflets (and other heart valves). The fibrotic cusps pull away from each other toward the periphery, leaving the center of the valve open during diastole (i.e. regurgitation is inevitable). On other occasions, the valve leaflets may also fuse to each other, causing a mixed picture of stenotic and insufficient valves. Large vessel vasculitides such as Takayasu arteritis, Giant cell arteritis, and Baçhet disease can result in post-inflammatory lesions of the aorta and its valve that can result in chronic valvular incompetence. Also, let’s not forget the connective tissue disorders discussed earlier (Marfan and Ehlers-Danlos syndromes) that can also affect the aortic valve. 

Unlike the sudden onset of symptoms with acute aortic regurgitation, chronic aortic regurgitation is typified by a long period of latency. During this time, the patient remains asymptomatic thanks to several compensatory mechanisms. This includes increasing the heart rate to reduce the afterload in the heart. However, once symptoms begin to manifest, there is a subsequent rapid deterioration of the patient status. Patients often report that they are becoming increasingly – and uncomfortably – aware of their heartbeat. They then begin to develop symptoms similar to those observed in acute aortic regurgitation. There are many clinical signs associated with this disorder including:

  • Wide pulse pressures – the difference between the systolic and diastolic blood pressures often exceed 100 mmHg.
  • Low diastolic blood pressure – below 60 mmHg
  • Becker’s sign – best seen on fundoscopy with the visible throbbing of the retinal vessels during systole
  • de Musset sign – is the rocking of the head with each heartbeat.

The associated murmur is a high-pitched, diastolic murmur that is best appreciated at the upper left sternal edge. In some instances, as blood rapidly re-enters the left ventricle, it hits the anterior mitral valve leaflet and closes the valve ahead of time. This produces a rumbling, low-pitched, mid-diastolic sound called an Austin-Flint murmur. Other murmurs of mitral and tricuspid insufficiency may also be present as a long-standing disease and may compromise those valves as well. 

Pulmonary regurgitation

The principal issue underlying pulmonary (or pulmonic) insufficiency is similar to that of the regurgitant disorders of the other valves. Blood flows backward from the pulmonary artery into the right ventricle. Any disorder that causes damage to the valve leaflets or widening of the valve annulus will result in regurgitation. There is seldom a primary lesion affecting the pulmonary valve resulting in valvular insufficiency. Instead, pulmonary insufficiency is more commonly a complication of pulmonary hypertension. It is, however, seen in congenital cardiac disorders like tetralogy of Fallot.

Although possible, it is far less likely to see pulmonary insufficiency as a complication of carcinoid heart disease, infective endocarditis, or rheumatic fever.
Pulmonary hypertension (PH) is an umbrella term that refers to raised blood pressures within the lung vasculature. The five causes of pulmonary hypertension have been termed the Pulmonary Hypertension World Health Organization Groups (PH WHO Groups). These include:

Pulmonary hypertenson WHO groups
Group 1: Pulmonary Arterial Hypertension (PAH) Narrowing of the pulmonary arterioles secondary to atherosclerotic changes. This can be:
- Mild – walls are thick and non-compliant
- Moderate – intimal hypertrophy and worsening of the narrowed lumen
- Severe – plexiform plaque formed with thrombi
Group 2: PH secondary to Left Heart Failure Pooling of blood in the left ventricle due to poor output and subsequent valvulopathy (i.e. mitral regurgitation). Types of left heart failure include:
- Systolic dysfunction – dilated left ventricle is unable to contract adequately
- Diastolic dysfunction – hypertrophic left ventricle does not adequately relax
Both cause increase ventricular pressure → Mitral regurgitation → Increased left atrial pressure and dilatation → PH
Group 3: PH secondary to Lung Disease  PH caused by:
- Restrictive lung disease, e.g. fibrosis, interstitial lung disease
- Obstructive lung disease, e.g. emphysema, chronic obstructive pulmonary disorder
- Miscellaneous, e.g. chronic exposure to high altitudes, obstructive sleep apnea, obesity hypoventilation syndrome
Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Elements of Virchow’s triad (stasis, endothelial injury, and hypercoagulability) → deep vein thrombus formation → recurrent embolization of small clots → occlusion of small vessels in the lungs → increased pulmonary pressures
Group 5: PH of Unknown Origin This miscellaneous group includes the following disorders whose pathophysiology with respect to PH is poorly understood:
- Sickle cell anemia
- Splenectomy
- Chronic hemolytic anemia
- Sarcoidosis
- And others


The symptoms and signs of pulmonary insufficiency overlap with that of right heart failure that was mentioned earlier. Additionally, in the presence of right ventricular hypertrophy (as a result of the need for increased workload) there is a palpable heave at the lower left sternal edge. The effect of a severely prolapsed pulmonary valve closing can also be felt in the second left intercostal space at the sternal edge. This phenomenon is called a palpable P2.

The pulmonic insufficiency murmur occurs in early-diastolic, is low-pitched, and best heard at the upper left sternal edge. There is an associated wide split of the second heart because of the disparity in the closure of the semilunar valves. The P2 component is also very loud and may overshadow the A2 component of S2. In instances when the pulmonary pressures exceed 60 mmHg (i.e. severe PH), an early diastolic, gradually decreasing (decrescendo), high-pitched murmur can be auscultated between the mid to upper left sternal edge. This is a Graham Steell murmur that results from the rapid reflux of blood through the prolapsed pulmonary valve. It is similar to the murmur of aortic regurgitation, but the peripheral signs associated with the latter are absent. 

Valvular stenosis

The word stenosis originated from the Greek word stenos, which means ‘narrow’. In the medical field, stenosis refers to any abnormal narrowing of a luminal cavity within the body. Since the heart valves are essentially orifices that allow blood to move from one chamber to the other, any reduction in the diameter of the pathway is referred to as a stenotic valvular disease. More specifically, either congenital anomalies of the cusps, pathological processes affecting the leaflets, or abnormal stiffening or shortening of the chordae tendineae (or papillary muscles) can result in decreased compliance of the valve leaflets.

Mitral stenosis

Age-related degenerative changes are one of the leading causes of mitral valve stenosis. It is similar to aortic stenosis where there is chronic mechanical stress of the valve that promotes the process of calcific degeneration. This is an age-related physiological response to repetitive mechanical stress, where calcium-based salts are deposited within the native tissue. The difference between mitral and aortic calcific degeneration is that the process affects the annulus of the mitral valve, but the leaflets of the aortic valve are unaffected. However, the most common cause of mitral stenosis is a post-inflammatory response to rheumatic fever (and its sequel of rheumatic heart disease, discussed earlier). This process may occur years after the initial insult. There is associated thickening, calcification, commissural fusion, and retraction of the leaflets that result in the valve being narrowed and non-compliant.

While the mitral valve may remain functional in the presence of annular calcification, there are cases where stone-like, ulcerated, irregular nodules may impede valve opening. Additionally, the nodules may burrow into the endocardium and disrupt the atrioventricular node and its associated system. Also, due to the irregularity of the nodules, they can act as a nidus for thrombus development and infective endocarditis. However, patients tend not to become symptomatic until the area of the valve orifice has decreased to about half its original size. 

Mitral stenosis can be the preceding factor in the development of left atrial enlargement (and subsequent atrial fibrillation), pulmonary hypertension, and subsequent right heart failure (with associated pulmonary and tricuspid valvular incompetence). The symptoms that patients often complain about are those related to these disorders, namely:

  • Exertional dyspnea develops in the early stages, but this may progress to dyspnea at rest.
  • Syncopal episodes due to the arrhythmias.
  • Embolic events due to atrial fibrillation.
  • Left atrial enlargement can also cause compression of the recurrent laryngeal nerve, leading to hoarseness.
  • Hemoptysis resulting from the pulmonary congestion.

The signs elicited on the clinical examination will overlap with those seen in other valvular disorders. This is because it is possible to have concomitant valvular lesions; since one disorder may precipitate the other. On palpation, there may be a left parasternal heave as well as a palpable impulse from the closure of the pulmonary valve (i.e. palpable P2). On auscultation, the first heart sound is loud and associated with an opening snap. The first heart sound becomes less intense as the leaflets become less pliable. Note that since the patient is likely to develop pulmonary hypertension, there may be a wide split of S2 as a result of pulmonary incompetence. The actual murmur of mitral stenosis is a rumbling, low-pitched, diastolic murmur. It’s best detected at the apex with the patient in the left lateral position. Note that this murmur occurs after the opening snap, is made worse by physical activity, and decreases with rest. The Graham Steell murmur of pulmonary incompetence and the pansystolic tricuspid regurgitant murmur may also be heard.

Tricuspid stenosis

In developed countries, the prevalence of tricuspid stenosis is quite low. This valvulopathy is the result of morphological changes to the valve leaflets that reduces the area of the valve orifice. Subsequently, there is an impedance to the flow of blood from the right atrium to the right ventricle; and by extension to the pulmonary vasculature and left side of the heart. The worldwide prevalence of the disease is also low. However, there are peaks in the number of individuals presenting with clinically significant stenosis where there is a concomitant prevalence of rheumatic fever. Though the most prominent culprit, rheumatic heart disease isn’t the only cause of tricuspid stenosis. Other disorders such as carcinoid syndrome (discussed earlier), systemic lupus erythematosus (Liebmann-Sachs lesions), and infective endocarditis (infected vegetation at the commissures) have been documented as less common etiologies. There is a female predominance in the acquired form of tricuspid stenosis, but males more commonly present with congenital tricuspid stenosis.

Most patients present with fatigue as their chief complaint. This is a direct result of the decreased cardiac output due to the right ventricular inflow obstruction. The associated right atrial dilatation distorts the electrical circuitry of the heart and precipitates atrial fibrillation. Other symptoms of right heart failure may develop as the disease progresses. With significant dilatation, the right atrium becomes palpable at the right sternal border. The murmur of tricuspid stenosis is heard at the lower left sternal edge during diastole. It increases with inspiration and is associated with a wide split of S1. 

Aortic stenosis

Of all the lesions affecting the heart valves, aortic stenosis is by far the most common one. Its prevalence increases with age; and with the dramatic improvement in health care over the past years, it is becoming more common as individuals are living longer. The disorder is also known as senile calcific aortic stenosis and is characterized by calcification of the aortic leaflets. The calcification starts within the cusps and gradually extends on upper surfaces and into the aortic sinuses (sinuses of Valsalva). The mass effect of the calcified nodules will then impede the opening of the cusps and therefore decrease the patent area of the valve orifice (from about 4 cm2 to 0.5 cm2 in severe cases). The pathogenesis of these valvular lesions lies in the continuous activity of the valve throughout a single lifetime. The valves undergo thousands of cardiac cycles each year without rest. The constant exposure to the high-pressure gradient and recurrent mechanism is coupled with inflammation, leading to calcific valve degeneration.

After many years of stenosis, the left ventricle will eventually undergo cardiac remodeling as the resistance to ventricular output increases the workload on the left side of the heart. Over time, the impact on the ventricle can also result in damage to the mitral valve (causing mitral valve prolapse), the left atrium (leading to left atrial dilatation), and the pulmonary vascular bed (pulmonary hypertension). There is left ventricular hypertrophy that can also make the chamber non-compliant; resulting in diastolic dysfunction. Therefore, aortic stenosis can create an environment for other valvular disorders. 

The onset of symptoms of aortic stenosis is delayed following the initial insult. There is a classic triad of chest pain, heart failure, and syncope. The chest pain results from decreased coronary perfusion and subsequent myocardial ischemia. Heart failure and its associated symptoms are a consequence of the left ventricular remodeling described above. Finally, the syncopal episodes are due to falls in blood pressure and ventricular arrhythmias. On auscultation, it is likely to note either a normal or reduced first heart sound. The aortic component of the second heart sound may also be absent or reduced; which may give the false impression of a loud pulmonary component. There may also be reversed (paradoxical) splitting of the second heart sound as there is delayed closure of the aortic valve. The fourth heart sound is also present as a result of the left ventricular hypertrophy. However, the classic murmur of aortic stenosis is one that gradually gets loud then decreases in intensity (i.e. crescendo-decrescendo murmur). This low-pitched murmur is best heard at the upper right sternal edge.

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References:

  • Ajam, Tarek, and Tarek Helmy. "Pulmonary Regurgitation (Pulmonic Regurgitation): Practice Essentials, Background, Pathophysiology". Emedicine.Medscape.Com, 2018, https://emedicine.medscape.com/article/157639-overview#a1. Accessed 12 Jan 2019.
  • Careddu, Lucio et al. "Aortic Atresia With Interrupted Aortic Arch: A Combination Incompatible With Life?: Figure 1:". Interactive Cardiovascular And Thoracic Surgery, vol 21, no. 2, 2015, pp. 272-273. Oxford University Press (OUP), doi:10.1093/icvts/ivv077. Accessed 12 Jan 2019.
  • Dima, Claudia. "Mitral Stenosis: Background, Pathophysiology, Epidemiology". Emedicine.Medscape.Com, 2018, https://emedicine.medscape.com/article/155724-overview#a4. Accessed 12 Jan 2019.
  • Guyton, Arthur C, and John E Hall. Textbook Of Medical Physiology. 11th ed., Elsevier Saunders, 2007, pp. 106-109.
  • Jagia, Priya et al. "Aortic Atresia With Normal Sized Left Ventricle". Indian Journal Of Radiology And Imaging, vol 26, no. 4, 2016, p. 521. Medknow, doi:10.4103/0971-3026.195784. Accessed 12 Jan 2019.
  • Jelani, Qurat-ul-ain et al. "Mitral Valve Prolapse: Practice Essentials, Background, Pathophysiology". Emedicine.Medscape.Com, 2016, https://emedicine.medscape.com/article/155494-overview#a1. Accessed 12 Jan 2019.

Article, review and layout:

  • Lorenzo Crumbie
  • Francesca Salvador
  • Jana Vaskovic

Illustrators:

  • Heart valves (cadaveric dissection) - Prof. Carlos Suárez-Quian
  • Tricuspid valve in a cadaver - Prof. Carlos Suárez-Quian
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