Heart Views

REVIEW ARTICLE
Year
: 2022  |  Volume : 23  |  Issue : 1  |  Page : 16--21

Asymptomatic severe aortic stenosis: contemporary evaluation and management


Mohamed Salah Abdelghani1, Sundus Sardar2, Abdelhaleem Shawky Hamada1,  
1 Department of Adult Cardiology, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
2 Department of Internal Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar

Correspondence Address:
Dr. Abdelhaleem Shawky Hamada
Department of Adult Cardiology, Heart Hospital, Hamad Medical Corporation, Doha
Qatar

Abstract

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.



How to cite this article:
Abdelghani MS, Sardar S, Hamada AS. Asymptomatic severe aortic stenosis: contemporary evaluation and management.Heart Views 2022;23:16-21


How to cite this URL:
Abdelghani MS, Sardar S, Hamada AS. Asymptomatic severe aortic stenosis: contemporary evaluation and management. Heart Views [serial online] 2022 [cited 2022 Jul 3 ];23:16-21
Available from: https://www.heartviews.org/text.asp?2022/23/1/16/345322


Full Text



 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}

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.[6],[7] 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}

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.{Figure 1}{Table 3}

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}

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.[21],[22],[23] 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.[24],[25],[26]

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.[19],[27] Pulmonary hypertension is a sign of advanced disease stage and is a robust prognostic parameter in AS.[28],[29]

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.[30],[31] 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.[35],[36],[37],[38] 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,[20],[30],[31],[32] strain imaging,[21],[22],[23],[24],[25],[26] and cardiac MRI.[34],[35],[36],[37],[38],[39] 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.

References

1Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al. Calcific aortic stenosis. Nat Rev Dis Primers 2016;2:16006.
2Thourani VH, Suri RM, Gunter RL, Sheng S, O'Brien SM, Ailawadi G, et al. Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg 2015;99:55-61.
3Sevilla T, Revilla-Orodea A, San Román JA. Timing of intervention in asymptomatic patients with aortic stenosis. Eur Cardiol 2021;16:e32.
4Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. The Tromsø study. Heart 2013;99:396-400.
5Grimard BH, Larson JM. Aortic stenosis: Diagnosis and treatment. Am Fam Physician 2008;78:717-24.
6Dal-Bianco JP, Khandheria BK, Mookadam F, Gentile F, Sengupta PP. Management of asymptomatic severe aortic stenosis. J Am Coll Cardiol 2008;52:1279-92.
7Katayama M, Chaliki HP. Diagnosis and management of patients with asymptomatic severe aortic stenosis. World J Cardiol 2016;8:192-200.
8Chair BH, Co-Chair HJ, Bermejo J, Chambers JB, Edvardsen T, Goldstein S, 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. Eur Heart J Cardiovasc Imaging 2017;18:254-75.
9Rusinaru D, Malaquin D, Maréchaux S, Debry N, Tribouilloy C. Relation of dimensionless index to long-term outcome in aortic stenosis with preserved LVEF. JACC Cardiovasc Imaging 2015;8:766-75.
10Rusinaru D, Bohbot Y, Djelaili F, Delpierre Q, Altes A, Serbout S, et al. Normative reference values of cardiac output by pulsed-wave doppler echocardiography in adults. Am J Cardiol 2021;140:128-33.
11Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease: Developed by the Task Force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2022;43:561-632.
12Annabi MS, Touboul E, Dahou A, Burwash IG, Bergler-Klein J, Enriquez-Sarano M, et al. Dobutamine stress echocardiography for management of low-flow, low-gradient aortic stenosis. J Am Coll Cardiol 2018;71:475-85.
13Ribeiro HB, Lerakis S, Gilard M, Cavalcante JL, Makkar R, Herrmann HC, et al. Transcatheter aortic valve replacement in patients with low-flow, low-gradient aortic stenosis: The TOPAS-TAVI registry. J Am Coll Cardiol 2018;71:1297-308.
14Clavel MA, Dumesnil JG, Capoulade R, Mathieu P, Sénéchal M, Pibarot P. Outcome of patients with aortic stenosis, small valve area, and low-flow, low-gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol 2012;60:1259-67.
15Cueff C, Serfaty JM, Cimadevilla C, Laissy JP, Himbert D, Tubach F, et al. Measurement of aortic valve calcification using multislice computed tomography: Correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction. Heart 2011;97:721-6.
16Clavel MA, Messika-Zeitoun D, Pibarot P, Aggarwal SR, Malouf J, Araoz PA, et al. The complex nature of discordant severe calcified aortic valve disease grading: New insights from combined Doppler echocardiographic and computed tomographic study. J Am Coll Cardiol 2013;62:2329-38.
17Pawade T, Clavel MA, Tribouilloy C, Dreyfus J, Mathieu T, Tastet L, et al. Computed tomography aortic valve calcium scoring in patients with aortic stenosis. Circ Cardiovasc Imaging 2018;11:e007146.
18Mehrotra P, Jansen K, Flynn AW, Tan TC, Elmariah S, Picard MH, et al. Differential left ventricular remodelling and longitudinal function distinguishes low flow from normal-flow preserved ejection fraction low-gradient severe aortic stenosis. Eur Heart J 2013;34:1906-14.
19Lancellotti P, Donal E, Magne J, Moonen M, O'Connor K, Daubert JC, et al. Risk stratification in asymptomatic moderate to severe aortic stenosis: The importance of the valvular, arterial and ventricular interplay. Heart 2010;96:1364-71.
20Writing Committee Members, Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: Executive summary: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:450-500.
21Pellikka PA, Sarano ME, Nishimura RA, Malouf JF, Bailey KR, Scott CG, et al. Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up. Circulation 2005;111:3290-5.
22Lancellotti P, Magne J, Dulgheru R, Clavel MA, Donal E, Vannan MA, et al. Outcomes of patients with asymptomatic aortic stenosis followed up in heart valve clinics. JAMA Cardiol 2018;3:1060-8.
23Nishimura R, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57-185.
24Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739-91.
25Weidemann F, Herrmann S, Störk S, Niemann M, Frantz S, Lange V, et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577-84.
26Mele D, Censi S, La Corte R, Merli E, Lo Monaco A, Locaputo A, et al. Abnormalities of left ventricular function in asymptomatic patients with systemic sclerosis using Doppler measures of myocardial strain. J Am Soc Echocardiogr 2008;21:1257-64.
27Lancellotti P, Donal E, Magne J, O'Connor K, Moonen ML, Cosyns B, et al. Impact of global left ventricular afterload on left ventricular function in asymptomatic severe aortic stenosis: A two-dimensional speckle-tracking study. Eur J Echocardiogr 2010;11:537-43.
28Lancellotti P, Magne J, Donal E, O'Connor K, Dulgheru R, Rosca M, et al. Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. Circulation 2012;126:851-9.
29Magne J, Pibarot P, Sengupta PP, Donal E, Rosenhek R, Lancellotti P. Pulmonary hypertension in valvular disease: A comprehensive review on pathophysiology to therapy from the HAVEC Group. JACC Cardiovasc Imaging 2015;8:83-99.
30Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation 2003;107:984-91.
31Dweck MR, Boon NA, Newby DE. Calcific aortic stenosis: A disease of the valve and the myocardium. J Am Coll Cardiol 2012;60:1854-63.
32Chin CW, Shah AS, McAllister DA, Joanna Cowell S, Alam S, Langrish JP, et al. High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis. Eur Heart J 2014;35:2312-21.
33Treibel TA, López B, González A, Menacho K, Schofield RS, Ravassa S, et al. Reappraising myocardial fibrosis in severe aortic stenosis: An invasive and non-invasive study in 133 patients. Eur Heart J 2018;39:699-709.
34Treibel TA, Kozor R, Schofield R, Benedetti G, Fontana M, Bhuva AN, et al. Reverse myocardial remodeling following valve replacement in patients with aortic stenosis. J Am Coll Cardiol 2018;71:860-71.
35Chin CW, Messika-Zeitoun D, Shah AS, Lefevre G, Bailleul S, Yeung EN, et al. A clinical risk score of myocardial fibrosis predicts adverse outcomes in aortic stenosis. Eur Heart J 2016;37:713-23.
36Azevedo CF, Nigri M, Higuchi ML, Pomerantzeff PM, Spina GS, Sampaio RO, et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol 2010;56:278-87.
37Barone-Rochette G, Piérard S, De Meester de Ravenstein C, Seldrum S, Melchior J, Maes F, et al. Prognostic significance of LGE by CMR in aortic stenosis patients undergoing valve replacement. J Am Coll Cardiol 2014;64:144-54.
38Vassiliou VS, Perperoglou A, Raphael CE, Joshi S, Malley T, Everett R, et al. Midwall fibrosis and 5-year outcome in moderate and severe aortic stenosis. J Am Coll Cardiol 2017;69:1755-6.
39Dweck MR, Joshi S, Murigu T, Alpendurada F, Jabbour A, Melina G, et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J Am Coll Cardiol 2011;58:1271-9.
40Banovic M, Putnik S, Penicka M, Doros G, Deja MA, Kockova R, et al. Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: The AVATAR trial. Circulation 2022;145:648-58.
41Wei C, Li Z, Xu C, Yin T, Zhao C. Timing of surgery for asymptomatic patients with severe aortic valve stenosis: An updated systematic review and meta-analysis. Hellenic J Cardiol 2021;62:270-7.
42Ullah W, Gowda SN, Khan MS, Sattar Y, Al-Khadra Y, Rashid M, et al. Early intervention or watchful waiting for asymptomatic severe aortic valve stenosis: A systematic review and meta-analysis. J Cardiovasc Med (Hagerstown) 2020;21:897-904.
43Available from: http://clinicaltials.gov/. [Last accessed on 2022 Mar 10]