Aortic Stenosis

I. Aortic Stenosis: What every physician needs to know.

Aortic stenosis (AS) refers to any condition that narrows the orifice of the aortic valve. While once caused primarily by rheumatic heart disease, this etiology is now rare in developed countries where calcific disease is now the major cause.

Historically referred to as calcific degeneration, it is now clear that AS in the developed world accrues from a process much akin to atherosclerosis. Thus the initial plaque of AS has a lipid core surrounded by a fibrous cap and the AS lesion is part of an active inflammatory process that causes valve leaflet injury and eventual calcification.

Calcification of scores of AS plaques in turn causes the leaflets to stiffen, preventing the valve from opening while distorting its architecture, resulting in a stenotic valve orifice. Mild orifice narrowing is clinically silent. However, once the valve area is compromised to less than half its normal aperture, the left ventricle (LV) must generate progressively greater pressure (as the narrowing worsens with time) to drive blood past the narrowed orifice.

Pressure overload in turn is compensated by the development of concentric hypertrophy (LVH) that provides the increased muscle mass needed to generate the pressure demands of outflow obstruction. However, while LVH is initially compensatory it unfortunately also bears several pathologic consequences. These include limited coronary blood flow reserve and diastolic and systolic heart failure.

A. History Part I: Pattern Recognition:

The presence or absence of symptoms in AS represents a key demarcation point in the disease. The classic symptoms of AS are angina, syncope, and the symptoms of heart failure, primarily dyspnea.

The risk of sudden death prior to symptom onset is slight, less than 1% a year. However, once symptoms occur, the risk of sudden death increases precipitously to about 2% per month so that 75% of patients have died within 3 years of symptom onset unless the aortic valve is replaced (discussed below). Obviously the above-noted symptoms could be caused by many other diseases, raising the issue of when attribution to AS can be made. In general, once the aortic valve orifice has become narrowed to one third its normal orifice area of 3.0 cm2(i.e., 1.0 cm2), symptoms that occur are likely to be due to AS.

B. History Part 2: Prevalence:

The two major risk factors for developing AS are age and bicuspid aortic valve. Approximately 3% of patients over the age of 70 have significant AS. About 2% of the U.S. population is born with a bicuspid (instead of a tricuspid) aortic valve, of whom about one third will develop clinically significant AS. Hypertension and hypercholesterolemia also contribute to the risk of developing significant AS.

C. History Part 3: Competing diagnoses that can mimic Aortic Stenosis.

AS could be confused with other entities that cause LV outflow obstruction. These include hypertrophic cardiomyopathy (HOCM) and fixed supravalvular stenosis and fixed subvalvular stenosis. These conditions can be distinguished from true AS with near certainty during cardiac echocardiography.

D. Physical Examination Findings.

AS is usually suspected when the clinician hears a heart murmur. The murmur of AS is systolic ejection murmur heard loudest over the aortic area, radiating to the neck. It may be accompanied by a thrill.

As disease severity worsens, the murmur peaks in intensity progressively later until the peak loudness is at the very end of systole. As severity increases, murmur intensity may lessen because aortic flow decreases. The carotid upstrokes in AS are delayed in timing and reduced in volume.

The apical impulse is powerful and sustained. The simultaneous palpation of a strong apical beat and weakened carotid upstrokes indicates obstruction between the LV and the carotids and this obstruction is usually severe AS. If arrhythmia induces R-R interval variation, murmur intensity increases after longer pauses because stroke volume increases after such pauses. The Valsalva maneuver reduces LV inflow and output, thereby reducing the murmur’s intensity.

These maneuvers help distinguish AS from HOCM. While in both AS and HOCM murmur intensity increases after a long R-R interval, intensity increases during Valsalva in HOCM (because of increased outflow obstruction) while intensity decreases in AS. Other clues to the diagnosis of AS are found in the character of S2. In AS, S2 may become soft and single as the aortic valve neither opens nor closes well, leaving only the P2 component of S2. Or delayed emptying of the LV may lead to paradoxical splitting of S2.

E. What diagnostic tests should be performed?

Echocardiography is the diagnostic modality most widely used to make the diagnosis of AS. However, an EKG should be routine in the work-up of AS patients because it is important to establish baseline cardiac rhythm.

Evidence of LVH and of left bundle branch block may give nonspecific clues about disease severity. B-type natriuretic hormone (BNP) is increased in AS and may have prognostic import. However, the specific value for BNP at which prognosis worsens has not been established.

What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Echocardiography is the mainstay of AS diagnosis. Adequate images reveal aortic valve anatomy (severity of calcification, bicuspid versus tricuspid structure), the extent of LVH, inferences regarding LV systolic and diastolic function and the severity of disease (Figure 2). Doppler interrogation of the valve measures the transaortic jet velocity, a datum that helps establish AS severity.

Jet velocity >4.0 m/sec is generally assumed to indicate severe AS that is likely to progress to the onset of symptoms within 2 to 3 years. Or, if the patient is already symptomatic, the symptoms can be attributed to AS if this or higher jet velocity is present.

Jet velocity can be used to calculate the transvalvular pressure gradient (g) using the modified Bernoulli equation where g = 4 V2where V = jet velocity. The continuity equation can be used to calculate aortic valve area.

This equation makes use of the principle that blood flow must be equal (continuous) on either side of the aortic valve. Flow = area (A) × velocity (V) and A = F/V. Thus A1 × V1= A2× V2 . Rearranging the terms, A2 (AVA) = A1× V1/V2 (Figure 1). The currently used criteria for categorizing mild, moderate, and severe AS are shown in Figure 2.

Figure 1.

Equation makes use of the principle that blood flow must be equal (continuous) on either side of the aortic valve.

Figure 2.

Aortic stenosis.

It must be noted that transvalvular velocity is determined both by valve area and by stroke volume. Thus jet velocity by itself may be misleading in cases of low output seen in patients with small ventricles or in patients with LV dysfunction. Conversely jet velocity might overestimate severity in high output states, such as anemia or thyrotoxicosis. In some cases AS severity is obvious; in others all the data available including history, physical examination, valve area, and jet velocity must be used to properly assess the disease.

Low flow AS

The guidelines for classifying AS (Figure 2) are generally predicated upon “normal” aortic flow since jet velocity, gradient, and to some extent valve area are predicated upon flow. Calculated valve area narrows at lower flow either because of calculation errors or because less flow opens a stenotic (but not fixed orifice) to a smaller aperture.

In turn low flow in some AS cases accrues from poor systolic function (reduced EF) due to contractile dysfunction, increased afterload, or both. Or low flow may occur when remodeling leads to a small hypertrophied ventricle with reduced stroke volume.

Both groups have poorer than normal prognosis. In the low EF group, inotropic stimulation with dobutamine often increases cardiac output. In some cases increased output increases gradient with little change in valve area.

Such patients have true aortic stenosis and their inotropic reserve portends better prognosis than if inotropic reserve were absent. In other patients, cardiac output increases but gradient does not so that calculated valve area increases dramatically. Such patients have aortic pseudo-stenosis and probably do better with medical management.

In the normal EF, low flow, small volume group, a small valve area together with heavy valve calcification suggest that the AS is severe and if the patient is symptomatic (severe symptomatic AS) outcome is better with surgery than without it.

Occasionally, discrepancies between the clinical assessment and the echocardiogram or discrepancies among echo data themselves require the need for additional information obtained from invasive hemodynamics to arrive at a diagnosis. Cardiac catheterization is performed to obtain a transvalvular pressure gradient and cardiac output, data used to calculate valve area using the Gorlin formula that converts valve gradient to velocity. AVA= F/√ 2gh, where g = acceleration due to gravity (converting mm Hg into force) and h = the mean pressure gradient. Flow must be expressed during the time the valve is open. Thus AVA = CO/44.3 √h.

III. Management.

A. Immediate management.

Medical therapy

AS is a mechanical obstruction to LV outflow and it has only one effective therapy, aortic valve replacement (AVR).Many patients may also have hypertension that must be controlled cautiously in view of the limited ability for cardiac output to increase if peripheral resistance decreases from antihypertensive medication.

Less than severe AS. Patients with less than severe AS require no specific therapy. As noted above the lesion of AS resembles that of atherosclerosis. This similarity engendered several clinical trials investigating whether statins, agents so effective in treating coronary disease, might also retard the progression of AS. While all such trials failed to show benefit of statins in slowing the progression of AS, other targets of medical therapy might be developed in the future.

Patients with less than severe AS should be seen yearly for a standard history and physical, and should undergo repeat echocardiography every 2 years to ascertain progression of disease.

Mechanical intervention

Severe asymptomatic AS. As noted above, the truly asymptomatic patient with AS has a relatively benign course until symptoms occur. However, there are some higher risk groups of asymptomatic AS where the risk of observation may exceed that of AVR. These include patients with poor exercise tolerance on a formal exercise test, patients with a jet velocity >5.0 m/sec, patients with severe valvular calcification, patient whose follow-up has demonstrated rapid progression of disease, patients with severe LVH, and probably patients with increasing levels of B-type natriuretic hormone. In centers where operative risk for isolated AVR in asymptomatic patients without other significant comorbidities is <1%, AVR for asymptomatic AS with one or more of the above risk factors is reasonable.

Symptomatic patients with severe AS. As noted above, the risk of death in such patients is extreme and even observation for 6 months as might occur between doctor appointments might be associated with a 10 % risk of sudden death. Thus prompt AVR is required when symptoms develop. There is no other effective therapy.

SAVR vs TAVR. Valve replacement is usually performed during open heart surgery (SAVR), which is the current gold standard of care. However, for patients deemed either inoperable or at high or intermediate surgical risk, transcatheter valve replacement (TAVR) either from the femoral or transapical approach offers a life-saving effective alternative to SAVR. This exciting technology is evolving rapidly with devices becoming easier and safer to deploy, continuously changing their risk/benefit ratio with regard to SAVR.

B. Physical Examination Tips to Guide Management.

As AS worsens, the murmur peaks progressively later in systole when maximum contraction produces maximum flow. The carotid upstrokes become more delayed in nature, and S2 may become single as A2 is lost. However, practically speaking few would rely on physical examination to detect AS progression in the modern era when echocardiography can so accurately, safely, and inexpensively follow the progress of the disease.

C. Common Pitfalls and Side-Effects of Management

Failure to use and integrated approach to the diagnosis

For the AS patient with angina and a mean transvalvular gradient of 80 mm Hg, the diagnosis is clear as are the management options. But for the patient with mean gradient of 35 mm Hg, a calculated valve area of 1.0 cm2 and questionable symptoms of dyspnea, the decision about whether to proceed to AVR cannot be made on the basis of any single finding alone. The degree of valve calcification and leaflet mobility, valve area, mean gradient, exercise performance, ejection performance, BNP, and possibly the response to dobutamine challenge may all be needed to ascertain if the patient’s AS is severe and whether his or her symptoms are being caused by the AS, in which case AVR is indicated.

Failure to comprehend the strengths and weaknesses of AVR

Patients are often not referred for surgery because physicians fail to recognize the safety of AVR in the modern era. An 80-year-old man with an EF of 50% who had previous bypass surgery now undergoing an elective AVR for dyspnea due to severe AS in the absence of pulmonary and renal disease has an operative risk of <3.0%. On the other hand, patients with severe lung renal disease on dialysis may be unsuitable for either SAVR or TAVR. In this regard risk score analysis is available on line and takes less than 2 minutes to calculate. The Society of Thoracic Surgeons (STS) score is probably the most accurate in predicting real world outcomes.

IV. Management with Co-Morbidities

Aortic stenosis is a disease of aging and the U.S. population becomes hypertensive at the rate of about 1% per year of life so that by age 80 about 80% of the population has hypertension including those patients with AS. Hypertension can be safely treated in this population but therapy must be cautious in view outflow obstruction at the aortic valve.

Blood pressure = cardiac output × total peripheral resistance (TPR). A pharmacologically mediated fall in TPR may not be compensated by an increase in cardiac output, potentially leading to hypotension. While no specific drug or drug combination is recommended in treating the AS patient with hypotension, the dictum starts low and go slow applies.

What's the Evidence for specific management and treatment recommendations?

Carabello, BA, Green, LH, Grossman, W, Cohn, LH, Koster, JK, Collins, JJ. “Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure”. Circulation. vol. 62. 1980. pp. 42-8. (Develops the framework for understanding reduced systolic function in AS.)

Dumesnil, JG, Pibarot, P, Carabello, BA. “Paradoxical low flow and/or low gradient severe aortic stenosis despite preserved left ventricular ejection fraction: implications for diagnosis and treatment”. Eur Heart J. vol. 31. 2010. pp. 281-9. (A good review of low flow low gradient AS.)

Rossebo, AB, Pedersen, TR, Boman, K. “SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis”. N Engl J Med. vol. 359. 2008. pp. 1343-56. (Introduces the concept of attempts to intervene in the progression of AS.)

Rosenhek, R, Zilberszac, R, Schemper, M. “Natural history of very severe aortic stenosis”. Circulation. vol. 121. 2010. pp. 151-6. (Emphasizes risk stratification in asymptomatic AS patients.)

Leon, MB, Smith, CR, Mack, M. “Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery”. N Engl J Med. vol. 363. 2010. pp. 1597-607. (Introduces TAVR in a large randomized trial.)

Mack, MJ1, Leon, MB2, Smith, CR2. “5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial”. Lancet. vol. 385. 2015. pp. 2477-84. (Presents 5 year TAVR follow-up for the Edwards SAPIEN valve.)

Adams, DH, Popma, JJ, Reardon, MJ. “Transcatheter aortic-valve replacement with a self-expanding prosthesis.”. N Engl J Med. vol. 370. 2014. pp. 1790-8. (Presents the large RCT for the other commercially available TAVR.)

Leon, MB, Smith, CR, Mack, MJ. “Transcatheter or surgical aortic-valve replacement in intermediate-risk patients”. vol. 374. 2016. pp. N Engl J Med-20. (Most recent RCT in the TAVR vs SAVR field. Found SAVR and TAVR equivalent in intermediate risk (STS average 6) patients and that TAVR was superior to SAVR when TAVR can be accessed from the femoral approach.)

Carabello, BA. “George Ohm and the changing character of aortic stenosis: it’s not your grandfather’s Oldsmobile”. Circulation. vol. 125. 2012. pp. 2295-7.