**Abstract**

Approximately 40% of patients with aortic stenosis (AS) show discordant Doppler-echocardiographic parameters with aortic valve area (AVA) <1 cm2 and/or index iAVA <0.6 cm2 /m2 (consistent with severe AS) and the mean gradient (MG) <40 mmHg, consistent with mild/moderate AS. Accurate diagnosis of true severe low flow low gradient AS versus pseudo-severe aortic stenosis is important for prognosis and optimal timing for intervention. Doppler echocardiography using intravenous low dose dobutamine challenge is widely used for differentiating pseudo-severe from true severe aortic stenosis. However, relying on echocardiography alone may have limitations in accurate diagnosis. Reliable diagnosis using echocardiography is dependent on multiple factors like the angle of interrogation of the aortic jet, the assumption that the LVOT area is circular in cross section, optimal echo windows, the presence of underlying subclinical coronary artery disease prior to dobutamine challenge etc. In this chapter, we describe non-invasive and invasive strategies to assess the aortic valve using dobutamine stress. Direct measurement of gradients across the aortic valve while estimating the change in cardiac output and aortic valve area with increments of dobutamine infusion dose is complementary, safe and useful when conventional echocardiography techniques are inconclusive. Finally, the chapter describes effective strategies of treatment for low gradient severe aortic stenosis, including the role for diagnostic balloon valvuloplasty, in the era of transcatheter valve replacement (TAVR).

**Keywords:** balloon aortic valvuloplasty, dobutamine stress test, low flow low gradient severe aortic stenosis, pseudo-severe aortic stenosis, trans-catheter aortic valve replacement

#### **1. Introduction**

Degenerative calcific aortic stenosis (AS) is the commonest primary valvular heart disease responsible for approximately 85,000 valve replacement procedures and 15,000 deaths per year in North America [1].

The diagnosis and staging of AS is primarily based on symptoms and Doppler echocardiography. AS is considered severe when the patient has a mean transvalvular gradient >40 mmHg, a peak aortic jet velocity >4 m/s, an aortic valve area (AVA) <1.0 cm2 , indexed aortic valve area (iAVA) <0.6 cm<sup>2</sup> /m2 and a dimensionless velocity index <0.25 [2–4].

However, in up to 40% of patients with AS, there is discordance between aortic valve area (<1 cm2 suggesting severe AS) and transvalvular gradients (<40 mmHg suggesting non-severe AS) on Doppler echocardiography [5–7]. These patients are referred to as having "low gradient" severe AS. Most of these patients have a "low flow state" across the aortic valve, which is defined as an indexed stroke volume <35 ml/m<sup>2</sup> . Many of these patients may be quite advanced in the natural history of severe AS. Despite challenges in establishing accurate diagnosis, "low gradient" severe AS patients tend to have poorer outcomes compared to patients with "high gradient" severe AS. This chapter describes the etiology, classification, diagnosis and management options of low flow low gradient (LFLG) severe AS.

#### **2. Classification of aortic stenosis**

All major guidelines have classified aortic stenosis based on hemodynamic parameters, symptoms and the left ventricular (LV) systolic function (**Figure 1**). According to the American College of Cardiology/American Heart Association, severe aortic stenosis is classified into asymptomatic severe AS (stage C) and symptomatic severe AS (stage D). Asymptomatic severe AS depending on LV function is further sub classified into stage C1—with normal LV function and stage C2—with reduced LV function (left ventricular ejection fraction (LVEF) <50%). Symptomatic severe AS is sub classified into three stages depending on blood flow across the aortic valve and hemodynamic characteristics (**Figure 2**). Normal flow (>35 ml/m2 ), high gradient (>40 mmHg), severe AS (AVA <1 cm2 /iAVA <0.6 cm/m2 ) is the most easily recognized entity with little diagnostic confusion (stage D1).

Low flow low gradient (LFLG) severe aortic stenosis (stages D2 and D3) represents an advanced stage in the hemodynamic spectrum of severe AS with poor prognosis and higher surgical morbidity and mortality than normal flow high gradient severe AS [8–12].

Although not incorporated into guidelines some authors recognize another variant called normal flow low gradient severe AS. This is a relatively poorly defined entity with unclear pathophysiology. Apart from measurement errors, one proposed explanation is that these patients have reduced arterial compliance (stiff arteries), which leads to a faster arterial wave reflection from the periphery. The

**9**

<1.0 cm2

**Figure 2.**

*from Clavel et al. [32].*

*Low Flow Low Gradient Severe Aortic Stenosis: Diagnosis and Treatment*

early reflection of the arterial wave at the end of systole may dampen the transvalvular gradients, independent of transvalvular flow. This phenomenon may, in part, explain the small AVA and low gradient discordance observed in patients with

*Subtypes of low-gradient aortic stenosis. AS, aortic stenosis; AVA, aortic valve area; LVEF, left ventricular ejection fraction; MG, mean transvalvular gradient; SVi, stroke volume index. Reproduced with permission* 

**2.1 Low flow low gradient severe AS with reduced ejection fraction (stage D2)**

This entity is found in about 5–10% of patients with severe AS. It is more prevalent in men, and is very often associated with coronary artery disease [13].

severe AS progresses over several years, the left ventricle responds to the increase in afterload by concentric left ventricular hypertrophy. This compensatory mechanism helps the left ventricle pump against an increase in afterload as well as offset the increase in wall tension. The compensatory mechanism is reflected in the natural history of aortic stenosis where patients with severe AS who are truly asymptomatic have a relatively long symptom free period. However onset of symptoms indicates a significant turning point in the natural history with poor prognosis when left untreated (**Figure 3**). The average life expectancy for patients with severe AS is 2 years for those with shortness of breath, 3 years for patients with syncope, and

Patients who start out as normal flow high gradient severe AS eventually transform into LFLG severe AS with reduced LVEF through a number mechanisms (**Figure 4**). The long standing persistent left ventricular hypertrophy leads to oxygen supply demand mismatch, reduced capillary density, chronic subendocardial ischemia and interstitial fibrosis. Another important reason for LV dysfunction is coexistent coronary artery disease seen in a majority of these patients—49–76% [8, 9, 12].

Eventually the left ventricle fails to keep up with the high pressure gradients and decompensates due to the afterload mismatch. The LV dilates, stroke volumes drops

and mean aortic valve gradient <40 mmHg [2]. As

, LVEF <50%, AVA

LFLG severe AS is defined as indexed stroke volume <35 ml/m2

/m2

*DOI: http://dx.doi.org/10.5772/intechopen.84435*

normal flow, low gradient severe AS.

/iAVA <0.6 cm2

5 years for those with angina [16].

*Low Flow Low Gradient Severe Aortic Stenosis: Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.84435*

**Figure 2.**

*Aortic Stenosis - Current Perspectives*

**2. Classification of aortic stenosis**

valve area (<1 cm2

<35 ml/m<sup>2</sup>

(>35 ml/m2

gradient severe AS [8–12].

However, in up to 40% of patients with AS, there is discordance between aortic

. Many of these patients may be quite advanced in the natural history

suggesting non-severe AS) on Doppler echocardiography [5–7]. These patients are referred to as having "low gradient" severe AS. Most of these patients have a "low flow state" across the aortic valve, which is defined as an indexed stroke volume

of severe AS. Despite challenges in establishing accurate diagnosis, "low gradient" severe AS patients tend to have poorer outcomes compared to patients with "high gradient" severe AS. This chapter describes the etiology, classification, diagnosis

All major guidelines have classified aortic stenosis based on hemodynamic parameters, symptoms and the left ventricular (LV) systolic function (**Figure 1**). According to the American College of Cardiology/American Heart Association, severe aortic stenosis is classified into asymptomatic severe AS (stage C) and symptomatic severe AS (stage D). Asymptomatic severe AS depending on LV function is further sub classified into stage C1—with normal LV function and stage C2—with reduced LV function (left ventricular ejection fraction (LVEF) <50%). Symptomatic severe AS is sub classified into three stages depending on blood flow across the aortic valve and hemodynamic characteristics (**Figure 2**). Normal flow

), high gradient (>40 mmHg), severe AS (AVA <1 cm2

is the most easily recognized entity with little diagnostic confusion (stage D1). Low flow low gradient (LFLG) severe aortic stenosis (stages D2 and D3) represents an advanced stage in the hemodynamic spectrum of severe AS with poor prognosis and higher surgical morbidity and mortality than normal flow high

Although not incorporated into guidelines some authors recognize another variant called normal flow low gradient severe AS. This is a relatively poorly defined entity with unclear pathophysiology. Apart from measurement errors, one proposed explanation is that these patients have reduced arterial compliance (stiff arteries), which leads to a faster arterial wave reflection from the periphery. The

and management options of low flow low gradient (LFLG) severe AS.

suggesting severe AS) and transvalvular gradients (<40 mmHg

/iAVA <0.6 cm/m2

)

**8**

**Figure 1.**

*Stage of aortic stenosis—adapted and modified from Nishimura et al. [2].*

*Subtypes of low-gradient aortic stenosis. AS, aortic stenosis; AVA, aortic valve area; LVEF, left ventricular ejection fraction; MG, mean transvalvular gradient; SVi, stroke volume index. Reproduced with permission from Clavel et al. [32].*

early reflection of the arterial wave at the end of systole may dampen the transvalvular gradients, independent of transvalvular flow. This phenomenon may, in part, explain the small AVA and low gradient discordance observed in patients with normal flow, low gradient severe AS.

### **2.1 Low flow low gradient severe AS with reduced ejection fraction (stage D2)**

This entity is found in about 5–10% of patients with severe AS. It is more prevalent in men, and is very often associated with coronary artery disease [13]. LFLG severe AS is defined as indexed stroke volume <35 ml/m2 , LVEF <50%, AVA <1.0 cm2 /iAVA <0.6 cm2 /m2 and mean aortic valve gradient <40 mmHg [2]. As severe AS progresses over several years, the left ventricle responds to the increase in afterload by concentric left ventricular hypertrophy. This compensatory mechanism helps the left ventricle pump against an increase in afterload as well as offset the increase in wall tension. The compensatory mechanism is reflected in the natural history of aortic stenosis where patients with severe AS who are truly asymptomatic have a relatively long symptom free period. However onset of symptoms indicates a significant turning point in the natural history with poor prognosis when left untreated (**Figure 3**). The average life expectancy for patients with severe AS is 2 years for those with shortness of breath, 3 years for patients with syncope, and 5 years for those with angina [16].

Patients who start out as normal flow high gradient severe AS eventually transform into LFLG severe AS with reduced LVEF through a number mechanisms (**Figure 4**). The long standing persistent left ventricular hypertrophy leads to oxygen supply demand mismatch, reduced capillary density, chronic subendocardial ischemia and interstitial fibrosis. Another important reason for LV dysfunction is coexistent coronary artery disease seen in a majority of these patients—49–76% [8, 9, 12].

Eventually the left ventricle fails to keep up with the high pressure gradients and decompensates due to the afterload mismatch. The LV dilates, stroke volumes drops

#### **Figure 3.**

*(A) Natural history as reflected by event-free survival in asymptomatic patients with AS. Initial aortic jet velocity (Vmax) stratifies patients according to the likelihood that symptoms requiring valve replacement will develop over time [14]. (B) Outcomes with very severe AS. Kaplan-Meier event-free survival rate for patients with a peak aortic jet velocity of 4.0 m/s or greater [15]. In both A and B, most "events" consisted of the onset of symptoms warranting aortic valve replacement.*

#### **Figure 4.**

*Factors leading to transformation of high gradient severe aortic stenosis to low flow low gradient severe aortic stenosis with reduced ejection fraction.*

**11**

**Figure 5.**

*severe aortic stenosis.*

*Low Flow Low Gradient Severe Aortic Stenosis: Diagnosis and Treatment*

the presence of a low flow (stroke volume index <35 ml/m2

and LVEF falls. As the flow across the stenosed aortic valve declines, the ability of the valve to open (which is flow dependent) reduces and hence the calculated aortic valve area is low. The pressure gradients across the valve are measured by modified

velocity of the aortic jet). Since flow velocities decline along with the stroke volume, the measured pressure gradients also drop exponentially. This leads to LFLG severe AS, with overall poor prognosis and a consensus class IIa recommendation for aortic

**2.2 Low flow low gradient severe AS with preserved left ventricular ejection** 

As opposed to patients with "classic" LFLG AS with reduced LVEF, those with "paradoxical" LFLG AS have preserved LVEF. This entity is defined as an LVEF >50%,

LFLG pattern is seen in 5–15% of patients with severe AS and is more prevalent in women and elderly patients. These patients have excessive LV hypertrophy in response to the hemodynamic stress. As a result they have small LV cavities and hence a low stroke volumes despite the preserved LVEF. Other factors (**Figure 5**) that contribute to low forward flow across the aortic valve include mitral regurgitation/ stenosis, tricuspid regurgitation/stenosis, atrial fibrillation and infiltrative cardiomyopathies like amyloidosis. Paradoxical LFLG AS shares clinical, pathological and hemodynamic similarities with heart failure with preserved ejection fraction. Both conditions are characterized by significant concentric left ventricular hypertrophy

*Factors leading to transformation of high gradient severe aortic stenosis to paradoxical low flow low gradient* 

, and a mean aortic valve gradient <40 mmHg [2, 5, 17].

, *P*, transaortic valve pressure gradient; *V*, maximum

), an AVA <1.0 cm2

,

*DOI: http://dx.doi.org/10.5772/intechopen.84435*

Bernoulli's equation (*P* = 4*V*<sup>2</sup>

valve replacement (AVR).

**fraction (stage D3)**

/m2

an iAVA <0.6 cm2

*Low Flow Low Gradient Severe Aortic Stenosis: Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.84435*

*Aortic Stenosis - Current Perspectives*

**10**

**Figure 4.**

*stenosis with reduced ejection fraction.*

**Figure 3.**

*symptoms warranting aortic valve replacement.*

*(A) Natural history as reflected by event-free survival in asymptomatic patients with AS. Initial aortic jet velocity (Vmax) stratifies patients according to the likelihood that symptoms requiring valve replacement will develop over time [14]. (B) Outcomes with very severe AS. Kaplan-Meier event-free survival rate for patients with a peak aortic jet velocity of 4.0 m/s or greater [15]. In both A and B, most "events" consisted of the onset of* 

*Factors leading to transformation of high gradient severe aortic stenosis to low flow low gradient severe aortic* 

and LVEF falls. As the flow across the stenosed aortic valve declines, the ability of the valve to open (which is flow dependent) reduces and hence the calculated aortic valve area is low. The pressure gradients across the valve are measured by modified Bernoulli's equation (*P* = 4*V*<sup>2</sup> , *P*, transaortic valve pressure gradient; *V*, maximum velocity of the aortic jet). Since flow velocities decline along with the stroke volume, the measured pressure gradients also drop exponentially. This leads to LFLG severe AS, with overall poor prognosis and a consensus class IIa recommendation for aortic valve replacement (AVR).
