Asymptomatic Severe Aortic Stenosis: Contemporary Evaluation and Management.

Aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries and most prevalent in the elderly. According to the current guidelines, intervention is recommended in symptomatic severe AS; however, in asymptomatic patients, aortic valve replacement (AVR) is considered when symptoms appear or the left ventricular dysfunction occurs, but the evidence supports these indications are poor. The optimal timing and modality of intervention in asymptomatic severe AS (ASAS) remain controversial. Earlier AVR in certain scenarios has been increasingly supported by some groups before subclinical irreversible myocardial damage occurs. In addition, the continuous advancement of percutaneous and surgical approaches where associated with a substantial decrease in mortality and perioperative complications which made many authors advocate for early intervention in those patients. Our review highlights the contemporary evaluation and management of ASAS and summarizes the current scientific evidence regarding optimal timing for intervention and indications for early AVR in such patients. Copyright:

INTRODUCTION

Aortic stenosis (AS) is the most common valvular heart disease in developed countries and most prevalent in the elderly. With the aging population in developed countries, a two-fold increase is anticipated in the next two decades. Most of these elderly patients are asymptomatic and are incidentally identified to have a systolic murmur or abnormal findings on the electrocardiogram.[1]

Despite the perpetual increase in the global health care burden of AS, there are no preventive or disease-modifying medical treatments. The only curative intervention is aortic valve replacement (AVR), which bears multiple risks. Consequentially, the optimal time and modality of intervention in patients with asymptomatic severe AS (ASAS) are controversial.[2]

Premature intervention may predispose individuals to unnecessary risks of AVR, while irreversible cardiac damage, with resultant heart failure (HF) or even death, may precede delayed intervention. Thus, for the optimal management of the populations with ASAS, a vigilant approach to this increasing dilemma and careful consideration must govern decisions for treatment, keeping in mind patient preferences and targeted goals of possible prognostic predictors.[3]

EPIDEMIOLOGY AND PREVALENCE

There is significant geographical variability in the relative frequency of AS causes. Rheumatic valvular disease is the most common in developing countries and often presents with concurrent involvement of mitral and aortic valve disease. In Europe and North America, the primary cause of aortic valve disease is calcific involvement of the congenital bicuspid valve or native trileaflet valve.[4]

A prospective study of 3273 participants, of which 164 patients had AS, concluded that the prevalence of AS increases with age, varying from 9.8% at 80–89 years, 3.9% at 70–79 years, 1.3% from 60 to 69 years, and 0.2% at 50–59 years of age.[5]

DIAGNOSTIC WORKUP

Initial workup for ASAS includes electrocardiography, chest X-ray, complete blood count, serum electrolyte levels, cardiac biomarkers, and multiple imaging modalities [Table 1]. The aim is to predict patients with rapid hemodynamic progression who may benefit from valve replacement even before developing clinical symptoms or left ventricular (LV) dysfunction.

Table 1

Diagnostic investigations for asymptomatic severe aortic stenosis[6]

ECG, chest X-ray, CBC, serum electrolytes, cardiac biomarkers

Echocardiography/Doppler: Disease severity and progression

Exercise testing: Confirm asymptomatic status

Dobutamine stress echocardiography in patients with low-gradient severe AS with reduced EF: Differentiates true from false severe AS

Cardiac magnetic resonance imaging: Evaluate the presence of cardiac midwall late gadolinium enhancement

ECG: Electrocardiogram, CBC: Complete blood count, EF: Ejection fraction, AS: Aortic stenosis

Two-dimensional or Doppler echocardiography is the standard imaging modality for the diagnosis of ASAS to evaluate its etiology, severity of valve calcification, coronary artery orifice position, segmental wall motion abnormalities, and any coexistent myocardial disease or valvular heart disease.[67] The current international recommendations for the echocardiographic evaluation of patients with AS depending on the measurement of the mean pressure gradient (the most robust parameter), peak transvalvular velocity (Vmax), and valve area.[8]

Although the valve area is theoretically the ideal measurement for assessing severity, there are many technical limitations. Clinical decision-making in discordant cases should therefore take into account additional parameters: functional status, stroke volume, Doppler velocity index,[9] degree of valve calcification, LV function, the presence or absence of LV hypertrophy, flow conditions, and the adequacy of blood pressure (BP) control during the study.[8] Low flow is arbitrarily defined by a stroke volume index ≤35 mL/m2 a threshold that is under current debate.[10]

Four broad categories can be defined according to gradient, flow, and ejection fraction (EF), with valve area <1 cm2 (≤0.6 cm2/m2) in all conditions [Table 2].[11]

Table 2

Categories of aortic stenosis according to gradient, flow, and ejection fraction

Category	Mean gradient (mmHg)	Valve area (cm2)	Other parameters	Comments
High-gradient AS	≥40	≤1	Peak velocity: ≥4.0 m/s	Assume severe AS regardless of LV function or flow parameters
Low-flow, low-gradient AS with reduced EF (LVEF <50%)	<40	≤1	SVI: ≤35 mL/m2	Low-dose DSE is recommended to differentiate between true severe and pseudo-severe AS.[12] Utility in elderly patients is unclear as assessed only in small registries[13]
Low-flow, low-gradient AS with preserved EF (≥50%)	<40	≤1	SVI: ≤35 mL/m2	Commonly in hypertensive elderly patients with small LV size and marked hypertrophy[9] and low stroke volume. CCT assessment to ascertain the degree of valve calcification is recommended[14-17]
Normal-flow, low-gradient AS with preserved EF (≥50%)	<40	≤1	SVI: >35 mL/m2	Usually moderate AS [1618]

AS: Aortic stenosis, EF: Ejection fraction, LVEF: Left ventricular ejection fraction, SVI: Stroke volume index, LV: Left ventricular, DSE: Dobutamine stress echocardiography, CCT: Coronary commuted tomography

CURRENT GUIDELINES INDICATIONS FOR VALVE REPLACEMENT[11]

In cases of ASAS, intervention is advised in patients with systolic EF <50% without another identifiable etiology (class IB recommendation), if symptoms develop on exercise testing (class IC), or sustained reduction in BP of more than 20 mmHg during exercise testing (class IIa, C).[11] In patients with low procedural risk, intervention is recommended in patients with EF >55% in the presence of one of the following parameters: very severe AS (mean gradient 60 mmHg or Vmax >5 m/s), severe valve calcification as per CCT assessment and Vmax progression 0.3 m/s/year, markedly increased brain natriuretic peptide (BNP) levels three times the age-and sex-corrected normal range and without other plausible explanations. The indications for AVR in ASAS [Table 3] can be used to guide the management of ASAS [Figure 1] by early surgical intervention (transcatheter aortic valve implantation or surgical AVR [SAVR]) or watchful waiting with meticulous patient education and reassessment at regulated intervals.

Table 3

Indications for aortic valve replacement in asymptomatic severe aortic stenosis[11]

LVEF <50% (Class Ib recommendation)

Low surgical risk, with decreased exercise tolerance or fall in SBP ≥20 mmHg from baseline to peak exercise evident on exercise testing (Class Ic)

Very severe AS (mean gradient ≥60 mmHg, aortic velocity of ≥5 m/s) and low surgical risk (Class IIa)

High-gradient severe AS with low surgical risk and serial testing reveals an incremental increase in aortic velocity ≥0.3 m/s per year (Class IIa)

Severe AS and low surgical risk with BNP level>3 times the normal range (Class IIa)

LVEF: Left ventricular ejection fraction, SBP: Systolic blood pressure, AS: Aortic stenosis, BNP: Brain natriuretic peptide

Figure 1

Management of severe AS, adapted from ESC/EACTS guidelines.[11] a: STS-PROM/EuroScoreII <4%, b: STS-PROM/EuroSCOREII >8%, and c: refer to Table 4

As per the latest European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) valvular guidelines 2021,[11] asymptomatic patients with severe AS who do not have an indication for intervention, watchful waiting is a safer and more appropriate strategy unless they have one or more of the predictors of rapid hemodynamic progression which can switch the patient management strategy to early surgical intervention instead of watchful waiting as they face a higher risk of adverse outcomes[19] [Table 4].

Table 4

Predictors of symptom development and adverse outcomes in asymptomatic severe aortic stenosis

Clinical characteristics (older age, atherosclerotic risk factors)

Pro-BNP >3 folds of normal value in serial follow up measurements[20]

Peak velocity >5 m/s [2021]

Rapid progression of AS severity (peak jet velocity increase>0.3 m/s/year) [2223]

Increase in mean gradient >20 mmHg with exercise

Severe LV hypertrophy[24]

Decreased indexed stroke volume

Valvuloarterial impedance >5 mmHg/ml/m2

Reduced LV global longitudinal strain >14.7%

Increased left atrial size (a′: Peak late diastolic velocity by tissue <9 cm/s)

Reduced mitral annular systolic (s’) and late diastolic velocities (a’)

Systolic pulmonary artery pressure >60 mmHg

Mid-wall LGE on cardiac magnetic resonance imaging

AS: Aortic stenosis, LV: Left ventricular, LGE: Late gadolinium enhancement, Pro-BNP: Pro-B-type natriuretic peptide

Confirmation of the absence of symptoms in patients with ASAS can be assessed by exercise testing, which also allows the assessment of exercise-induced physiological changes.[20]

Although the AHA/ACC guidelines did not comment on the role of biomarkers in AS, the ESC/EACTS guidelines currently indicate that valve replacement is reasonable (Class IIa) in an asymptomatic patient with markedly elevated levels of natriuretic peptide three times greater than the normal range after correction for age and gender, confirmed by repeated measurements and without alternative explanations.[20]

Reduced LV global ventricular strain is an early marker of subclinical myocardial dysfunction when EF is still preserved and is also associated with the presence of myocardial fibrosis.[212223] The risk of death for patients with an absolute global longitudinal strain (GLS) >–14.7% is 2.5-fold higher in a recent individual participant data meta-analysis.[242526]

Left atrial size increases with worsening diastolic dysfunction, reflects the magnitude and the chronicity of increased LV filling pressure, and is associated with adverse cardiac events in patients with AS.[1927] Pulmonary hypertension is a sign of advanced disease stage and is a robust prognostic parameter in AS.[2829]

Histopathological studies have shown that the two key processes which drive LV decompensation and the transition from hypertrophy to HF are progressive myocyte death and myocardial fibrosis.[3031] Levels of high-sensitivity troponin-I (hsTnI) now allow detection of low-level myocyte cell death and injury due to a range of different cardiovascular conditions beyond myocardial infarction (MI). In patients with AS, hsTnI levels relate not to the burden of coronary artery disease but instead to the magnitude of the hypertrophic response and the presence or absence of myocardial fibrosis.[32]

Cardiac magnetic resonance imaging (MRI), on the other side, can detect areas of replacement fibrosis in patients with AS using the widely applied late-gadolinium enhancement (LGE) technique.[33] A midwall pattern of LGE is observed, which can be differentiated from scarring due to other causes such as MI and cardiac amyloidosis. This pattern is also associated with multiple other markers of LV decompensation, including advanced LV hypertrophy, reductions in diastolic and systolic function, increased symptomatic status, and reduced exercise capacity.[34]

Once it initially develops, further midwall LGE accumulates rapidly in the ventricle and is irreversible despite AVR.[34] As a consequence, the myocardial scarring that patients develop while waiting for AVR persists for the long term, potentially worsening myocardial health and adverse events well beyond valve intervention. Consistent with this hypothesis, midwall LGE has been confirmed as a powerful long-term prognostic marker in several independent studies.[35363738] This occurs in a dose-dependent manner, with the more LGE, the higher the rates of adverse cardiovascular events.[39] A rationale is therefore evolving to consider whether AVR should be performed when midwall LGE is first identified to prevent further progression of fibrosis and to improve long-term clinical outcomes.

RECENT TRIALS AND NEW FRONTIERS IN MANAGEMENT

In the recently published randomized controlled AVATAR trial of 157 patients, those with ASAS early surgery were associated with a significantly lower incidence of adverse events and was associated with a 54% relative risk reduction in primary composite outcomes of all-cause death, acute MI, stroke, or unplanned hospitalizations for HF over a median follow-up period of 32 months as compared to conservative management. This randomized trial adds growing clinical and prognostic benefits to support performing early SAVR once AS is severe, regardless of the presence of symptoms or LV dysfunction.[40] These results are important as the current guidelines do not recommend upfront surgical interventions in patients without symptoms or reduced LV EF. A limitation of the AVATAR trial is the small number of patients.

In a meta-analysis of eight studies (2021) including one randomized controlled trial (RCT) and seven observational studies (OSs) enrolling 2462 patients. In the OSs, early surgery showed a significant reduction in all-cause mortality and cardiac death in asymptomatic patients with severe AS which was further intensified in the RCT. This meta-analysis also supported that early surgery is associated with better outcomes for patient with ASAS.[41] Another meta-analysis of eight studies (2020) including 2201 patients showed that early AV replacement either surgical or transcatheter was associated with lower all-cause mortality and cardiovascular mortality when it was compared to the conservative strategy of waiting for symptoms. Furthermore, a subgroup sensitivity analysis comparing severe AS with very severe AS supported the same benefit of early intervention with valve replacement.[42]

Potential benefits of early intervention can be explained by the fact that it is done before subclinical myocardial dysfunction and irreversible myocardial damage and fibrosis happen. Supportive data showed that those irreversible changes could be detected by cardiac markers,[20303132] strain imaging,[212223242526] and cardiac MRI.[343536373839] If early valve replacement is done before irreversible myocardial damage happens, then the prognosis, as well as perioperative outcome, would be more favorable.

There are currently ongoing RCTs comparing SAVR or transcatheter AVR (TAVR) versus (wait for symptoms strategy) in ASAS patients using high-risk features of hemodynamic progression; either echocardiographic criteria as left atrial dilatation, diastolic dysfunction, GLS in addition to Pr0-BNP (DANAVR),[43] or using cardiac MRI criteria of midwall fibrosis (EASY-AS and EVOLVED) Trials.[43] These trials have relatively longer follow-up periods.

Furthermore, other currently ongoing RCTs evaluating the role of TAVR in asymptomatic severe aortic valve stenosis patients versus watchful waiting (EARLY TAVR T) in terms of mortality as an endpoint;[43] moreover, TAVR in HF patients with moderate AS in comparison to optimized HF therapy (TAVR UNLOAD).[43] The results of those ongoing trials when published will further shed the light on the role of early valve intervention in these patient populations.

CONCLUSION

ASAS is fairly common in clinical practice and requires an extensive workup. A multidisciplinary team approach and patient preference are essential in the management to identify the criteria of rapid hemodynamic progression and decide on either a watchful waiting strategy or valve replacement. The team must take into consideration the patient's general status, laboratory, echocardiographic parameters as well as cardiac MRI, which can all predict the risk and benefits of each management strategy. As per the latest ESC guidelines, in the absence of a clear indication for intervention as well as other predictors for the development of symptoms and potential outcomes [Table 4] then, the watchful waiting approach is recommended. However, recently published newer trials are supporting the early intervention approach, especially in the presence of adverse outcome predictors, and these may alter the clinical practice in the near future and tip the scale toward early surgical or transvalvular catheter replacement in patients with ASAS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.