Low-Gradient, Low Ejection Fraction Severe Aortic Stenosis: Still a Management Conundrum

Abstract

The management of patients with severe symptomatic aortic stenosis and a high transvalvular gradient is straightforward. It requires aortic valve replacement. Management of aortic stenosis patients with low flow, low ejection fraction and low gradient is fraught. Such patients rarely fulfill all the tenets of “severity” and also have severe left ventricular dysfunction. Both circumstances make the outcome of aortic valve replacement uncertain. Thus the management of this group of patients requires integration of all diagnostic modalities available. The physical examination, degree of valve calcification, the appearance of the valve during sonographic examination and the presence of inotropic reserve all contribute importantly in judging stenosis severity and the likelihood of successful valve replacement.

Main article text

Introduction

A 78-year-old patient cannot walk 50 feet to collect the morning newspaper without stopping to relieve dyspnea. His exercise tolerance has progressively worsened during the past 2 years. He also notes two-to-three pillow orthopnea and occasional ankle edema but no angina or syncope.

• Medication: furosemide, 80 mg/day.

• Physical examination: pulse 80; blood pressure 100/76 mmHg.

• Central venous pressure 9 cmH₂O; carotid upstrokes mildly delayed and low in volume.

• Chest: clear.

• COR: grade 2/6 mid-late peaking systolic ejection murmur. S₂ physiologically split.

• Extremities: +1 ankle edema.

• Echocardiogram: poorly mobile heavily calcified aortic valve.

• Peak jet velocity 2.8 m/s, mean gradient 20 mmHg.

• Ejection fraction (EF): 0.22; aortic valve area (AVA) 0.7 cm²; B-type natriuretic peptide 480 pg/mL; STS 3.8.

Discussion

The patient has low-gradient, low-flow, low-EF aortic stenosis (AS). In normal individuals the 3.0-cm² aortic orifice area accommodates normal systolic flow with virtually no pressure gradient between the left ventricle (LV) and the aorta. Even when the AVA is reduced by half (1.5 cm²), the pressure gradient is usually less than 10 mmHg. However, further reduction in AVA leads to progressively greater transvalvular gradients, so an AVA of 1.0 cm² produces a pressure gradient of 25–40 mmHg, an AVA of 0.75 cm² causes a pressure gradient of 50–70 mmHg, and an AVA of 0.5 cm² causes a pressure gradient of more than 100 mmHg when LV stroke volume is normal. Wall stress (σ) is an indicator of the afterload on the LV, and is represented as σ = P × r/2th, where P is LV pressure, r is LV radius, and th is LV thickness. As AS increases the pressure term in the numerator, concentric hypertrophy (LV hypertrophy) can increase the thickness term in the denominator, maintaining normal afterload [1]. In some cases, LV hypertrophy is inadequate to normalize stress, afterload increases, impairing ejection, and EF is reduced [2]. However, in the case presented here, the peak LV pressure (systolic blood pressure plus peak gradient) is only about 120 mmHg; thus afterload is not likely to be excessive nor the cause of the profoundly impaired EF. Instead, EF is depressed because of severe LV contractile dysfunction, as the result of either long-standing pressure overload or a secondary cardiomyopathy or coronary artery disease, or some combination of the three [2]. Such patients pose a difficult clinical challenge; while most patients undergo aortic valve replacement (AVR) at a low operative risk, low-gradient, low-EF patients have an operative risk many times greater than that of high-gradient patients [3]. Poor prognosis in low-gradient, low-EF patients accrues from severe LV dysfunction that often does not abate after AVR. However, some low-gradient, low-EF patients do improve after AVR, and the clinical challenge is predicting this improvement after AVR.

Does Our Patient Have Severe Aortic Stenosis?

Severe AS is usually defined by an AVA of 1.0 cm² or less, a peak transaortic jet velocity of 4.0 m/s or greater, and/or a mean transvalvular pressure gradient of 40 mmHg or more [4]. However, as can be seen in Figure 1, these measures are often incongruous with each other [5]. Indeed, in a recent “real world” experience, 38% of patients had a mean gradient of less than 40 mmHg, consistent with the data presented in Figure 1. This discordance is especially true in low-flow states. In the presented case here, only the AVA fits the definition of severe AS, and the physical examination, which is key in such cases, is less than reassuring because several of the features of severe AS (late peaking murmur, single S₂) are lacking. However, the immobility and heavy calcification of the valve supports the diagnosis of severe AS [6].

Figure 1

The Relationship of Aortic Valve Area and Mean Pressure Gradient for More Than 3400 Patients with Aortic Stenosis.

The relationships predicted by the Gorlin formula (blue line) and actual data (yellow line) closely approximate one another. Importantly, 31% of patients (left lower quadrant and right upper quadrant) fail to meet both definitions of severe aortic stenosis. From Minners et al. [5].

Very Low Gradient

The definition of low-gradient, low-flow, low-EF is somewhat arbitrary. Prognosis worsens when stroke volume index is less than 35 mL/m², but obviously stroke volume is a continuous not a dichotomous variable [7]. The value of 35 mL/m² is most useful in defining study populations and less useful in clinical decision making. Because a mean gradient of 40 mmHg and/or an aortic valve peak jet velocity of 4 m/s have been used to define severe AS [4], values less than these in the face of an AVA of 1.0 cm² or less are often defined as corresponding to a low gradient. Both low flow in some studies [6] and a low gradient in others independently predict poor outcome [8]. However, prognosis is dramatically worse in patients with very low EF (<0.30) and very low mean gradient of 20 mmHg or less where LV dysfunction is extraordinarily severe [9].

Inotropic Reserve

Assessment of inotropic reserve is the best proven technique in helping to risk stratify low-gradient, low-EF patients for AVR [10]. Patients demonstrating an increase in stroke volume of 20% or more during dobutamine infusion have an approximately 10% operative risk (depending on other comorbidities) compared with three times that risk for patients without inotropic reserve. The test also helps separate patients with true AS from those with pseudo-AS. This latter condition is one in which a small AVA is calculated at low flow but in which AVA increases substantially at high flow (flow increases far more than gradient), presumably because greater flow opens a moderately but not severely stenotic valve to a wider aperture [11]. Because the valve is not severely stenotic, it seems unlikely that AVR would be of benefit, although it is possible that in such severely dysfunctional ventricles that even modest afterload reduction might be beneficial. It is likely that inotropic incompetence also impairs hemodynamic support in the immediate postoperative period, predisposing to low-output state. It is important to note that while lack of inotropic reserve impairs prognosis, some such patients do improve following AVR, making judgment about surgery in this group all the more difficult [12].

Myocardial Architecture

Assessment of myocardial composition and architecture may also be useful in stratifying risk in this group of patients. Extensive scarring from previous myocardial infarction or extensive fibrosis from long-standing pressure overload represents a void of contractile elements that cannot respond to afterload reduction from AVR. LV midwall fibrosis detected by late gadolinium enhancement during cardiac MRI helps predict a poor outcome in this group of patients [13].

Biomarkers

Biomarkers have been helpful in aiding prognosis in asymptomatic AS patients, and high levels of natriuretic peptides and troponin predict a poor prognosis in general. However, the group of low-gradient, low-EF patients invariably have heart failure, where the levels of biomarkers are inevitably elevated, making them less useful in prognosis for this group of AS patients.

Balloon Valvotomy

While dense calcification of the aortic valve in AS prevents balloon valvotomy (BAV) from providing durable increases in AVA in most patients, it does offer temporary relief in most. While the increase in AVA and decrease in gradient is only modest, in some patients this modest improvement may cause a significant although only temporary clinical improvement. Accordingly BAV is used in some cases as a trial bridge to definitive AVR [14]. While evidence for this technique is not robust, many investigators report substantial improvement following BAV that is then used as a bridge to AVR. BAV has been used both in profoundly ill inoperable patients who became operable after BAV-induced improvement and as a test to see whether definitive AVR was justified.

Transcatheter Aortic Valve Replacement

Transcatheter AVR (TAVR) could be an attractive therapy in low-gradient, low-flow, low-EF patients because it avoids the negative effects of the trauma of surgery and of requiring extracorporeal circulation. Data from a subset of the PARTNERS randomized trial found that low-flow AS patients had worse survival than normal-flow patients shown in Figure 2 [7]. However, low-flow AS patients had substantially better survival with TAVR than with so-called medical therapy, while survival was similar between surgical AVR and TAVR (Figure 2) [7]. Of interest would be a trial involving very low gradient (<20 mmHg) AS patients that randomized them to receive TAVR versus conservative therapy.

Figure 2

Survival rates.

(A) The survival of patients with inoperable low-gradient (LG), low-flow (LF), low ejection fraction (LEF) aortic stenosis treated with transcatheter aortic valve replacement (TAVR; solid line) versus medical management (MM; dotted line), where TAVR is superior to MM. (B) Similar outcome for TAVR (solid line) and surgical aortic valve replacement (dotted line) for high-risk surgical patients. From Herrmann et al. [7].

Our Patient

Our patient underwent a dobutamine infusion, achieving a peak jet velocity of 4.1 m/s. He subsequently underwent TAVR. He required brief inotropic support, but improved rapidly, going home on the fifth post-TAVR day. His predischarge echocardiogram found an EF of 0.40.

Conclusion

When low-flow, low-EF AS is due to a high gradient and thus high afterload, the results following AVR are good because AVR relieves the afterload excess immediately, improving LV performance. However, low-gradient, low-flow, low-EF AS is indicative of severe myocardial dysfunction. In some cases, function improves after AVR, in others it does not. Proof that AS is truly severe, that the gradient exceeds 20 mmHg, that there is inotropic reserve, and that there is minimal myocardial fibrosis leans toward a favorable outcome of AVR in AS patients. However, the next step in assessing this group of patients will be understanding the intrinsic myocardial properties that are responsible for myocardial recovery or its lack following relief of the AS-induced pressure overload.

References

1. GrossmanW, JonesD, McLaurinLP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 1975;56:5664.

2. CarabelloBA, GreenLH, GrossmanW, CohnLH, KosterJK, CollinsJJJr. Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure. Circulation 1980;62:428.

3. ConnollyHM, OhJK, SchaffHV, RogerVL, OsbornSL, HodgeDO, et al. Severe aortic stenosis with low transvalvular gradient and severe left ventricular dysfunction: result of aortic valve replacement in 52 patients. Circulation 2000;101:19406.

4. NishimuraRA, OttoCM, BonowRO, CarabelloBA, ErwinJP, GuytonRA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(22):243888.

5. MinnersJ, AllgeierM, Gohlke-BaerwolfC, KienzleRP, NeumannFJ, JanderN. Inconsistencies of echocardiographic criteria for the grading of aortic valve stenosis. Eur Heart J 2008;29(8):10438.

6. TastetL, Enriquez-SaranoM, CapouladeR, MaloufJ, AraozPA, ShenM, et al. Impact of aortic valve calcification and sex on hemodynamic progression and clinical outcomes in AS. J Am Coll Cardiol 2017;69(16):20968.

7. HerrmannHC, PibarotP, HueterI, GertzZM, StewartWJ, KapadiaS, et al. Predictors of mortality and outcomes of therapy in low-flow severe aortic stenosis: a placement of aortic transcatheter valves (PARTNER) trial analysis. Circulation 2013;127(23):231626.

8. BaronSJ, ArnoldSV, HerrmannHC, HolmesDRJr, SzetoWY, AllenKB, et al. Impact of ejection fraction and aortic valve gradient on outcomes of transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67(20):234958.

9. LevyF, LaurentM, MoninJL, MailletJM, PasquetA, Le TourneauT, et al. Aortic valve replacement for low-flow/low-gradient aortic stenosis operative risk stratification and long-term outcome: a European multicenter study. J Am Coll Cardiol 2008;51(15): 146672.

10. MoninJL, QuéréJP, MonchiM, PetitH, BaleynaudS, ChauvelC, et al. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics. Circulation 2003;108:31924.

11. NishimuraRA, GranthamJA, ConnollyHM, SchaffHV, HiganoST, HolmesDRJr. Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: the clinical utility of the dobutamine challenge in the catheterization laboratory. Circulation 2002;106(7):80913.

12. QuereJP, MoninJL, LevyF, PetitH, BaleynaudS, ChauvelC, et al. Influence of preoperative left ventricular contractile reserve on postoperative ejection fraction in low-gradient aortic stenosis. Circulation 2006;113(14):173844.

13. DweckMR, JoshiS, MuriguT, AlpenduradaF, JabbourA, MelinaG, et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J Am Coll Cardiol 2011;58:12719.

14. KeferJ, GapiraJM, PierardS, De MeesterC, GurneO, ChenuP, et al. Recovery after balloon aortic valvuloplasty in patients with aortic stenosis and impaired left ventricular function: predictors and prognostic implication. J Invasive Cardiol 2013;25(5):23541.