What Type of AS Does Your Patient Have? Sorting Out Differences in the Low-Flow, Low Gradient Severe AS Patients

Aortic stenosis (AS) in the United States is primarily due to senile calcific degenerative disease, followed by congenital aortic stenosis typically related to bicuspid aortic valves. As we rethink timing of intervention with the advent of transcutaneous aortic valve implantation and replacement (TAVR), the etiology and presentations become critically important considerations.

Though our initial understanding of aortic stenosis hemodynamics originated from experience in the cardiac catheterization laboratory, the general approach now relies very heavily on Doppler measurements by transthoracic echocardiography.¹ The main pillars of diagnosis and grading have been described in great detail in the guidelines and are as follows:

1)    Velocity

2)    Mean gradient

3)    Calculated aortic valve area (AVA)

4)    Indexed aortic valve area

5)    Dimensionless index

The simplest approach is to understand that there is an inverse relationship between velocity and valve area, meaning that as valve area decreases, there is an increase in transvalvular velocity. In the most straightforward cases, this leads to normal-flow, high-gradient severe aortic stenosis, which is characterized by an AVA <1.0cm² with a peak velocity >4 m/sec and mean gradient >40 mmHg. This classification of severe aortic stenosis accounts for the majority of AS cases, and there is little question regarding the validity of the diagnosis. 

Classifications of Severe Aortic Stenosis

Matters become more complicated when there is disagreement in staging by velocity, gradients, and aortic valve area. At the crux of this conundrum is that while these parameters are all used to describe aortic stenosis, they are not themselves interchangeable. The lack of perfect concordance is, therefore, expected and the aortic valve area becomes increasingly important, with intermediate velocities of 3.0 to 4.0 m/sec. We see that in the graphical representation (Figure 1) that there are some patients who will have severe aortic stenosis as defined by the AVA, but will not be associated with a severe gradient.²

With that in mind, we are left with three additional classifications of severe aortic stenosis: 1) classical low-flow, low-gradient severe AS; 2) paradoxical low-flow, low-gradient severe AS; and 3) normal-flow, low-gradient severe AS.^1,3

Severe AS or Pseudo-Severe AS?

In classical low-flow, low-gradient severe AS, the pathophysiology of the absence of high transvalvular velocities is attributed to poor stroke volume in the setting of reduced ejection fraction. The left ventricular (LV) dysfunction may be secondary to ischemia from concomitant coronary disease or perhaps chronic pressure overload and LV burnout, but regardless of etiology, it results in low stroke volume (defined as a stroke volume index <35 mL/m²). The clinician is presented with a diagnostic dilemma — is there true severe AS or is it a case of pseudo-stenosis? The mainstay of discriminating between the two has been the low-dose, dobutamine stress echocardiography in which dobutamine is administered in stages and transaortic valve gradients and AVA are assessed to determine if there is contractile reserve (i.e., increased cardiac output) and the true severity of the aortic valve once stroke volume increases. Another method of parsing out those at higher risk of truly stenotic aortic valves is the use of the gated computed tomography (CT)-derived aortic valve calcium score, which is particularly useful in the absence of contractile reserve on dobutamine stress echocardiography.

Paradoxical Low-Flow, Low-Gradient Severe AS

In paradoxical low-flow, low-gradient, severe AS, the ejection fraction (EF) is noted to be normal (EF >50%). The stroke volume is still found to be low, however, and the mechanism for this entity has been most commonly attributed to a concentrically hypertrophied ventricle with a small LV cavity. Diastolic dysfunction, sub-clinical LV dysfunction, elevated systemic blood pressure, small body habitus, and improper measurements have also been implicated. The usefulness of dobutamine stress echocardiography in this scenario has been suggested by some groups, though this has not reached mainstream practice as in the classical low-flow, low-gradient AS type. One provocative application of the dobutamine stress echocardiography in the evaluation of paradoxical low-flow, low-gradient, severe AS is in calculating the projected AVA for a predicted normal flow rate.⁴

Normal Flow, Low-Gradient AS and other measurement errors?

The last classification of severe AS is the problematic entity of normal-flow, low gradient aortic stenosis. Thus far, experts suggest many of these cases represent improper measurements, such as in the left ventricular outflow tract (LVOT) measurements, sub-maximal peak velocity detection, and imprecision in estimation of the LVOT cross-sectional area, as well as the presence of aortic or mitral regurgitation. The truth is that all of these technical issues plague the evaluation of every aortic stenosis study. 

As in most diagnoses, when either parameters for grading or symptoms are conflicting, the next step is typically cardiac catheterization with an invasively measured direct transvalvular gradient. Agreement between cardiac cath hemodynamics and echocardiography is also sometimes weakened due to several factors. For the most part, a peak-to-peak gradient is more traditionally used in the cath lab, while a peak maximal instantaneous gradient is obtained by echocardiography. The two points used for gradient calculations are often different. Echocardiography is also unable to assess for pressure recovery phenomenon, in which patients with small aortas (usually <30 mm in diameter) may see a reconstitution (i.e., small increase) of pressure within the ascending thoracic aorta, which may mitigate the negative hemodynamic impact of AS on end-organ perfusion.

Do Biomarkers Help?

Additional clinical markers may serve to further risk stratify patients that are suspected of having severe AS beyond the measured parameters, such as B-type natriuretic peptide (BNP), high-sensitivity troponin, exercise response, and elevated pulmonary pressures.⁵ Our current guidelines do include an inappropriate exercise response (e.g., reduction in blood pressure) or symptoms on symptom-limited exercise treadmill test as indications to proceed with aortic valve replacement (AVR) in an otherwise asymptomatic individual.⁶ An abnormal BNP, abnormal global longitudinal strain, pulmonary hypertension, and other clinical characteristics have been mentioned in the European guidelines as possible predictors of symptom development and adverse outcomes to consider in weighing the risks and benefits of surgical intervention for asymptomatic severe aortic stenosis.⁷

The Changing Timing of AVR

All of the pains taken to correctly classify patients with aortic stenosis are intended to properly risk stratify patients at high risk for death as well as to guide timing of intervention. To date, symptoms have been the major determinant of AVR timing, in addition to adverse ramifications on the left ventricle, in large part due to the work of Drs. Braunwald, Ross, and Morrow, who grappled with this very question in 1968 of determining the ideal time to send a patient with severe aortic stenosis to surgery for valve replacement.⁸ The results of their post-mortem analysis culminated in the well-known graph below (Figure 2), in which we can appreciate the inflection point at around 60 years old, when the development of symptoms heralds imminent demise of the following few years.

And yet, all of our historical and contemporary attempts to drill down on the true severity of aortic stenosis have been predicated on the notion of balancing the risks of untreated disease with the risks of surgical intervention. The advent of TAVR, however, represents a pivotal moment in the field of cardiology (and medicine in general) for the treatment of aortic stenosis. Now that valve replacement is much more appealing and available, especially to the highest-risk patients, the question then becomes, where is the sweet spot? Or when is it time to replace the stenotic valve in this current era?

Clinical trials are now ongoing to delve into how TAVR will continue to change the balance between risk and benefit for AS patients. That TAVR has a role in inoperable/high risk, as well as intermediate risk, patients with severe AS is without controversy. Registry data has looked into the use of TAVR in bicuspid aortic valve AS, with encouraging results for the newer valves. The TAVR-UNLOAD⁹ study seeks to further investigate if intervention on moderate aortic stenosis in patients with reduced EF would improve clinical outcomes, which is consistent with the rationale that even moderate AS can be detrimental as a cause of afterload on a weakened ventricle.

The ramifications of these studies are far-reaching. TAVR has introduced a new option for bioprosthetic aortic valve replacement, changing the course for inoperable patients. It is now an option for the treatment of degenerative and dysfunctional bioprosthetic surgical AVR (SAVR), which makes bio-SAVR a possibility for younger patients, and may suggest a significant change in the threshold for which treatment can be considered.¹⁰ We have already found from the TOPAS-TAVI trial¹¹ that TAVR in low-flow, low-gradient severe AS resulted in improvement in LV function, but that the presence of contractile reserve by dobutamine stress echocardiography was unable to reliably predict recovery or improvement, and further, the absence of contractile reserve did not portend negative consequences. The usefulness of low-dose dobutamine stress echocardiography may further lose ground if TAVR-UNLOAD finds that there is benefit to intervention on even moderate AS in the setting of reduced EF. This paradigm shift would be a huge departure from our traditional approach to the evaluation of AS. In many ways, these studies remind us to look at the Doppler data in context of the patient, rather than the numbers in isolation. 

Bottom Line

How we understand patients with AS has changed as the therapeutic approach has evolved. We continue to pursue better characterization of, and ability to, communicate the true severity of aortic stenosis in terms of flow and impact on the ventricle, as well as end-organ perfusion (Table 1, Figure 3). The line in the sand as to when to replace the aortic valve continues to shift earlier in the disease course, as the safety profile of the intervention improves. We can hardly wait for the next wave in percutaneous structural heart advances.

References

1. Baumgartner H, Hung J, Bermejo J, et al. Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2017 Apr; 30(4): 372-392.
2. Otto CM. Aortic stenosis: treat the patient not the numbers. Heart. 2018 Feb; 104(3): 190-191. doi: 10.1136/heartjnl-2017-312222. 
3. Pibarot P, Dumesnil JG. Low-flow, low-gradient aortic stenosis with normal and depressed left ventricular ejection fraction. J Am Coll Cardiol. 2012; 60: 1845-1853.
4. Blais C, Burwash IG, Mundigler G, et al. Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low flow, low-gradient aortic stenosis: The multicenter TOPAS (Truly or Pseudo Severe Aortic Stenosis) study. Circulation. 2006; 113: 711-721.
5. Dahou A, Clavel MA, Capoulade R, et al. B-type natriuretic peptide and high-sensitivity cardiac troponin for risk stratification in low-flow, low-gradient aortic stenosis: a substudy of the TOPAS study. JACC Cardiovasc Imaging. 2017 Sep 9. Pii:S1936-878X(17)30717-9.
6. Aortic Stenosis Writing Group, Bonow RO, Brown AS, Gillam LD, et al; Aortic Stenosis Rating Panel, Dehmer GJ, Bonow RO, Lindman BR, et al; Appropriate Use Criteria Task Force, Doherty JU, Dehmer GJ, Bailey SR, et al. ACC/AATS/AHA/ASE/EACTS/HVS/SCA/SCAI/SCCT/SCMR/STS 2017 Appropriate use criteria for the treatment of patients with severe aortic stenosis. J Am Soc Echocardiogr. 2018 Feb; 31(2): 117-147.
7. Baumgartner H, Falk V, Bax JJ, et al; ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017 Sep 21; 38(36): 2739-2791.
8. Ross J Jr, Braunwald E. Aortic stenosis. Circulation. 1968 Jul: 38(1 Suppl): 61-67.
9. Spitzer E, Van Mieghem NM, Pibarot P, et al. Rationale and design of the Transcatheter Aortic Valve Replacement to Unload the Left ventricle in patients with advanced heart failure (TAVR UNLOAD). Am Heart J. 2016 Dec; 182-188.
10. Otto CM, Baumgartner H. Updated 2017 European and American guidelines for prosthesis type and implantation mode in severe aortic stenosis. Heart. 2018 May; 104(9): 710-713.
11. Riberio HB, Lerakis S, Gilard M, et al. Transcatheter aortic valve replacement in patients with low-flow, low-gradient aortic stenosis: the TOPAS-TAVI registry. J Am Coll Cardiol. 2018 Mar 27; 71(12): 1297-1308.

¹Department of Cardiology, Veterans Administration Long Beach Health Care System, Long Beach, California; ²University of California, Irvine, California; ³Division of Medicine, Veterans Administration Long Beach Health Care System, Long Beach, California 

Disclosure: Dr. Kern reports he is a consultant for Abiomed, Merit Medical, Abbott Vascular, Philips Volcano, ACIST Medical, Opsens Inc., and Heartflow Inc. Dr. Jeannie Yu reports no conflicts of interest regarding the content herein.