Left-sided obstructive lesions generally have a male predominance, and studies have reported familial clustering.¹ The NOTCH-1 gene has been linked to the bicuspid aortic valve (BAV), aortic stenosis, and hypoplastic left heart syndrome.² A small study (38 probands) of family members of patients with hypoplastic left heart syndrome demonstrated that 19% of family members had congenital heart disease; of those, 72% were also left-sided obstructive lesions.³ In general, left-sided lesions are associated with one another and often occur together.

BAV occurs when, instead of the normal configuration of three cusps, two are partially or completely fused. The most
common orientation is fusion of the right and left cusps, followed by right and noncoronary, and least commonly left and noncoronary cusps.¹⁶ BAV may or may not have raphe and may simply have two cusps with either a horizontal or vertical orientation.

Unicuspid valves can also exist in which there are two sites of leaflet fusion or partial fusion, leaving a slit-like or keyhole like opening (Figure 107.1). Independent of the valve itself, there can also be annular hypoplasia in the setting of otherwise normal cusps leading to stenosis at the valvar level.

BAV stenosis occurs more frequently than BAV regurgitation. There is significant variability in the rate of valve disease progression in BAV, but nearly all affected patients develop calcification and some degree of valve dysfunction in the long-term. This is thought to be caused by shear stress and turbulent flow across the abnormal valve which promotes inflammation and myxomatous change, and stimulates osteogenic factors that lead to calcification.¹⁷ Those that tend to have more asymmetric cusps and with right and noncoronary fusion may develop calcification at a faster rate.¹⁶

The physiologic result of significant valvar aortic stenosis is elevated afterload against which the left ventricle (LV) must work. In response to this afterload, the LV hypertrophies to maintain wall stress at a constant, even in cases of severe stenosis leading to (1) diastolic dysfunction with elevated left ventricular filling pressures and (2) increased myocardial oxygen demand. Mismatch between coronary perfusion and myocardial oxygen demand can result in subendocardial ischemia and infarction. The subendocardium and papillary muscles are vulnerable to decreased perfusion, particularly with exercise. Holter monitoring has revealed ventricular dysrhythmias which, in combination with increased myocardial oxygen demand, can lead to sudden death.¹⁸

Subvalvular aortic stenosis typically consists of either a membranous circumferential ring or a fibrous ridge of tissue in the left ventricular outflow tract below the aortic valve (Figure 107.2) comprising collagen, myocytes, and elastin.¹⁹ The tissue may also have attachments to the mitral valve and its subvalvular apparatus or the aortic valve. Mitral valve abnormalities are associated with subvalvular aortic stenosis as well, including attachment of a papillary muscle to the interventricular septum or aortic leaflet, accessory mitral valve tissue, and muscularization of the subaortic portion of the anterior leaflet. Because this appears to be an acquired lesion, proposed mechanisms of development include abnormal endothelium and shear stress from congenital abnormalities in the left ventricular outflow tract.²⁰ The resulting physiology is similar to that outlined above in valvar aortic stenosis, with significant stenosis leading to elevated afterload and potential for left ventricular hypertrophy and dysfunction. In general, subvalvular aortic stenosis is progressive but the rate of progression is variable and can be stable for many years.²¹ Aortic valve regurgitation can result from turbulent flow in the presence of a subaortic membrane or ridge.²²

Supravalvular aortic stenosis develops just above the aortic valve and is related to abnormally thick, hypertrophied tissue consistent with the genetic abnormality of the elastin gene found in Williams syndrome. The most frequent site of stenosis occurs at the sinotubular junction, but it can also occur across the entire ascending aorta and transverse arch. Because of the proximity of the aortic valve cusp attachments to the sinotubular junction, these may also be thickened. Aside from the issues regarding coronary perfusion and myocardial demand mismatch noted above, patients with supravalvular aortic stenosis have additional risk factors for coronary ischemia. The coronary ostia, being located near or below the thickened sinotubular junction and just above abnormal aortic cusp attachments, can themselves be stenosed. Furthermore, narrowing distal to the coronaries not only exposes the coronary arteries to hypertension but also limits diastolic flow and perfusion, which could contribute to ischemia and sudden death.²³ Death in patients
with supravalvular aortic stenosis undergoing cardiac catheterization procedures has been reported, likely because of anesthesia and the resultant drop in diastolic blood pressure, as well as catheter manipulation near the coronaries.²⁴

CoA occurs when there is either discrete or long segment narrowing of the aortic arch or proximal descending aorta. The most common site for discrete coarctation is at the isthmus, the insertion site of the PDA that is present in fetal and early neonatal circulation. There are two common theories as to how coarctation develops. One theory proposes that the ductal tissue present in the PDA is also present in a larger portion of aortic tissue and, therefore, creates a discrete narrowing as this ductal tissue constricts and the PDA closes shortly after birth.²⁵ The other prevailing theory is that a state of low flow across the aortic arch in utero leads to poor growth and development of the aortic arch.²⁶ Both theories may be accurate in that discrete coarctations seem more likely to be explained by the ductal tissue theory whereas a longer segment of narrowing across the arch may be more likely to occur in a low-flow state.

When severe, patients can develop significant collateral vessels including the intercostal, internal mammary, and scapular arteries in order to provide flow to the body, bypassing the area of coarctation. The fixed obstruction can lead to otherwise similar problems seen in aortic stenosis including left ventricular hypertrophy and dysfunction over time. Hypertension also develops as the blood vessels to the head and neck are typically proximal to the obstruction and thus exposed to high pressure. The lower body, including the kidneys and mesentery, however, gets less perfusion pressure. The renin-angiotensin-aldosterone system is therefore stimulated to retain fluid and increase blood pressure, further propagating elevated pressures proximal to the obstruction.²⁷

An inherent vascular tissue abnormality is also likely present in patients with coarctation. The pathophysiology of the aorta in coarctation is notable for endothelial dysfunction and abnormal elastic properties even after repair.²⁸ Patients with CoA have also been found to have a higher rate of intracranial aneurysms (10%) than the general population,²⁹ thus supporting the concept of CoA as a diffuse arteriopathy.

Mitral stenosis can arise from a valve, or region above the valve, that is dysplastic. Mitral valve dysplasia typically involves thickened leaflets, a loss of interchordal space, and abnormalities of the papillary muscles. Parachute mitral valve is a specific type of dysplastic valve in which the mitral valve chordae all insert on a single papillary muscle, resulting in a parachute type of appearance that may or may not result in mitral stenosis. In supravalvular mitral stenosis, a membrane starts at the level of the mitral valve annulus, differentiating it from cor triatriatum which is a membrane located above the atrial appendage. A supramitral ring is another form of supravalvular mitral stenosis that can be circumferential and can extend to the mitral valve. As a result of obstruction to mitral inflow, the left atrial pressures may be elevated, depending on the degree of narrowing. This can lead to elevated pulmonary artery pressures, pulmonary edema, and ultimately elevated right heart pressures in cases of severe stenosis.

Many patients with BAV remain asymptomatic for many years. They may be referred for a murmur prior to the development of symptoms which include exertional angina, easy fatiguability, heart failure symptoms, syncope, or even sudden death.⁶,³⁰ Adults with severe aortic stenosis can remain asymptomatic despite this degree of disease. One study demonstrated that only 10% of patients with a gradient of >80 mm Hg had symptoms of angina.³¹ Those with higher gradients are more likely to
have symptoms, need intervention sooner, or experience death sooner than those with a relatively mild stenosis earlier in life.³² Patients with BAV also may present with aortic dilatation or dissection.

The physical examination may show an increased apical cardiac impulse, a presystolic tap of a forceful atrial contraction, and a palpable thrill in the suprasternal notch or precordium in cases of moderate-severe stenosis. The second heart sound may be single owing to prolonged ejection time across the aortic valve and in very severe cases, there may be paradoxical splitting (A2 occurring after P2). There may be an S4 in patients with severe stenosis and diastolic dysfunction. There is typically an early systolic ejection click (loudest at the left sternal border and apex). A click and a suprasternal notch thrill are highly suggestive that stenosis is valvar as opposed to subvalvular or supravalvular. The classic crescendo-decrescendo murmur is usually loudest at the right upper sternal border that peaks later as severity increases and radiates to the carotids. There may be a delayed and/or diminished carotid upstroke.

Subvalvular aortic stenosis may also be asymptomatic and present with a murmur. It could also be discovered on follow-up for another lesion such as CoA, VSD, or atrioventricular canal defect. Symptoms similar to that of valvar aortic stenosis with fatigue, heart failure symptoms, syncope, or angina may develop as stenosis progresses. The systolic murmur is usually loudest at the left midsternal border and radiates to the upper sternal border and suprasternal notch. There is not usually a systolic ejection click unless there is a coexistent BAV. If there is associated aortic regurgitation, a diastolic murmur at the left sternal border may also be heard.

Supravalvular aortic stenosis may be asymptomatic or may be found owing to a history of Williams syndrome or a murmur heard on examination. Symptoms may be similar to valvar aortic stenosis, with special concern in patients with angina and syncope, given the additional risks for coronary ischemia. There will be a murmur similar to valvar aortic stenosis, located at the right sternal border and radiating to the suprasternal notch and the carotids but without a preceding systolic ejection click.

The hallmark of presentation is typically asymptomatic hypertension. However, if there is severe hypertension, patients can present with headache, epistaxis, heart failure, or even aortic dissection. Patients may also experience claudication because of poor perfusion of their lower extremities. Unrepaired, the average age of death for those with CoA is 35 years, with cause of death including heart failure, aortic dissection, endarteritis, endocarditis, myocardial infarction, and intracranial hemorrhage.³³ The prevalence of stroke in contemporary CoA patients is not well-described, but these patients experience hemorrhagic and ischemic stroke at a significantly younger age compared to the general population.³⁴ The association of intracranial aneurysm and CoA is thought to be related to either developmental abnormalities of the arterial wall or pathologic changes as a result of mechanical forces attributable to hypertension.³⁵ Vascular abnormalities including vertebral artery hypoplasia and incomplete posterior circle of Willis are associated with increased cerebral vascular resistance. There is a significantly higher prevalence of both of these cerebral vascular abnormalities in CoA patients compared to the general population and is an independent risk factor for hypertension in this population, highlighting another potential mechanism linking stroke and hypertension in CoA.³⁶

On examination, lower extremity pulses may be decreased, delayed, or absent. There may also be a systolic murmur heard at the left upper chest under the clavicle radiating to the back representing turbulent flow across the area of narrowing. Cuff blood pressures can reveal lower blood pressure in the legs and hypertension in the arms. This may be variable depending upon the location of CoA in relation to the subclavian arteries. If distal to both the left and right subclavian arteries, as is typical, both arms will be hypertensive. However, if there is an anomalous subclavian artery or the coarctation is proximal to one of the subclavian takeoffs, then one arm or both may have blood pressure similar to those in the legs. There may also be continuous murmurs associated with collateral vessels.

Mitral stenosis may be largely asymptomatic depending on the degree of obstruction. Patients can present with symptoms of heart failure including dyspnea on exertion, orthopnea, and exercise intolerance, or new-onset atrial fibrillation. On examination, there may be a mid-diastolic and late diastolic murmur, usually low-pitched. There may also be a prominent S2 from pulmonary hypertension.