47. Mixed Aortic Valve Disease- Indications and Guidelines

Rohun Bhagat MD, Eric E. Roselli MD
Cleveland Clinic
February 28th, 2025

Abbreviations & Definitions

AI – Aortic insufficiency
AS – Aortic stenosis
AVR – Aortic valve replacement
LV – Left ventricle
LVEF – Left ventricular ejection fraction
LVESD – Left ventricular end-systolic diameter
LV-GLS – Left ventricular global longitudinal strain
MAVD – Mixed aortic valve disease
NYHA – New York Heart Association
RV – Right ventricle

Indications & Guidelines for Management

Aortic valve disease has long been addressed with surgical intervention through valve repair and replacement. There remains little debate on the benefit of aortic valve intervention for severe aortic stenosis (AS) and severe aortic insufficiency (AI).1 However, as the progressive nature of these disease states is better understood, it stands to reason that there may be utility in earlier intervention, particularly in patients who suffer concurrently from both AS and AI. At present, many practitioners manage patients based on the dominant lesion, and isolated moderate AS or AI does not serve as a primary indication for intervention.1,2 Specifically, for asymptomatic moderate AS, there is a Class IIb indication for aortic valve replacement (AVR) at the time of other cardiac surgery.1 Further, for moderate AI, there is a Class IIa indication for AVR at the time of other cardiac surgery.1 This chapter takes a more nuanced approach and discusses recommendations for intervention on mixed aortic valve disease, particularly for patients who have combined moderate AS and moderate AI.

When considering combined aortic valve disease, it is important to understand that the effects of mixed aortic valve disease are not simply additive between the isolated effects of AS and AI. Rather, the effects of concurrent AS and AI are synergistic in their damage to the cardiac infrastructure and are summarized below.3

  • Significant increase in LV afterload resulting from AS-related increase in systolic pressure and reduced aortic valve orifice area, and AI-related increase in flow, which increases the LV systolic blood pressure. This leads to LV hypertrophy, which may be more severe than in isolated AS or AI, leading to decreased LV compliance.3
  • A typical response to AI is for the LV to dilate to accommodate the increased end-diastolic volume (and thus mitigate any significant increase in LV end-diastolic pressure); however, concentric LV hypertrophy from AS limits the degree of LV dilation, therefore causing the volume overload of AI to disproportionately increase LV end-diastolic pressure.
  • Chronic elevation in LV filling pressures may lead to secondary pulmonary hypertension and left atrial dilation (which may subsequently result in RV dysfunction and atrial fibrillation).3 Of note, left atrial diameter and upstream remodeling have consistently been shown to be one of the strongest negative predictors of survival in patients with aortic valve disease.4-9
  • LV hypertrophy is associated with a reduction in coronary flow and the development of myocardial fibrosis.3
  • The combination of increased afterload and increased filling pressure is likely responsible for symptoms that occur in patients with MAVD, often occurring prior to the LVESD reaching 50 mm (which would be a Class IIa indication for AVR in isolated asymptomatic, severe AI with normal LVEF).3

Mixed aortic valve disease is not rare. A Swedish registry showed that mixed valvular heart disease accounted for 10% of all valvular disease.10 Additionally, AS was associated with AI in 18% of AI cases, while AI was associated with AS in 7% of AS cases.10 AS is often associated with degenerative progressive calcification, while AI is often associated with congenital abnormalities of the aortic valve leaflets, such as bicuspid and unicuspid aortic valves.10,11 Another study identified 524 patients who had asymptomatic MAVD. Of these patients, 130 (25%) had MAVD with moderate AS and moderate AI.12

Note that there are no published formal societal guidelines on recommendations for patients with moderate MAVD, to the best of our knowledge. Therefore, the following recommendations are primarily based on expert opinion. Additionally, the following recommendations refer to patients with MAVD who have moderate AS and moderate AI.

Multiple studies have shown the detrimental effects of moderate MAVD. It is therefore important to intervene on these patients in a timely fashion. For all patients with moderate MAVD, we strongly recommend a heart team discussion including cardiac surgery and cardiology. For symptomatic patients with moderate MAVD, we recommend intervention with AVR. For patients with moderate MAVD undergoing cardiac surgery for another reason, we strongly recommend concomitant AVR at the time of surgery. For asymptomatic patients with moderate MAVD, we recommend close monitoring for symptoms/progression of disease with echocardiography every 6 months and assessment of left ventricular and left atrial remodeling (e.g., LV-GLS, left atrial volume index, and left atrial reservoir strain). In these complex patients, valve intervention is best performed at a high-volume aortic valve center.21

Summary Table

Aortic Valve Pathology Recommendation Evidence
Combined moderate AS & moderate AI All patients: Strongly recommend heart team discussion including cardiac surgery and cardiology Symptomatic: Recommend intervention with AVR At time of other cardiac surgery: Strongly recommend concomitant AVR Asymptomatic: Monitor for symptoms/progression of disease with echocardiography every 6 months; assess for changes in LV function and markers of remodeling (e.g. LV-GLS); consider stress echocardiography Expert opinion

Supporting Evidence for Current Indications & Guidelines

Honda et al. 201213: Review of 306 patients with severe AS medically managed. 74 patients had moderate or severe AI, and 232 patients did not have significant AI. The mean follow-up was 4.5 years. Event-free survival (defined as survival without cardiac death or hospitalization because of heart failure) was lower in the group with concomitant AI. Concurrent moderate or severe AI was found to be an independent predictor of adverse events in patients who had severe AS.

Rashedi et al. 201412: 524 patients with asymptomatic MAVD who did not undergo early intervention (including patients with severe AS or AI). 190 patients had either moderate AS or AI (130/190 patients had moderate AS and moderate AI), and patients were followed over 5.5 years. Of 190 patients, 99 (52%) underwent AVR and 39 (22%) died during follow-up. 40/99 patients who underwent surgery had progressed to severe AS or AI in combination with symptoms, while 11/99 underwent AVR while asymptomatic or minimally symptomatic. Over the follow-up period, there was an expected decrease in aortic valve area and an increase in mean aortic valve gradient.

Lupinek et al. 202314: 81 patients with moderate AS and moderate AI. 40 (47%) had bicuspid or unicuspid aortic valves. 50 patients were asymptomatic. At a mean follow-up of 5.9 years, 20 patients died and 46 underwent AVR. 1, 2, and 5-year follow-up mortality rates were 3.5%, 7.1%, and 15.3%, respectively, and the rate of AVR was 23.5%, 30.6%, and 43.5%, respectively. Only 71.7%, 63.5%, and 47.1% were alive and free of AVR at 1, 2, and 5-year follow-up, respectively.

Egbe et al. 201615: 213 patients with no symptoms, normal LVEF, trileaflet aortic valves, and moderate/severe MAVD. Adverse events were defined as NYHA class 3/4 symptoms, AVR, or death. Mean follow-up was 10.1 years, and mean time to adverse event was 2.9 years. An adverse event endpoint was reached in 172/213 patients, and 69% of these events occurred in moderate MAVD. Event-free survival was 70%, 42%, and 30% in moderate/severe MAVD at 1, 3, and 5 years, respectively. The study compares these results to a separate paper on isolated severe AS, which showed an event-free survival of 67%, 56%, and 33% at 1, 2, and 4 years, respectively16. This is expanded on in their next study below.

Egbe et al. 201617: 251 patients with moderate MAVD (defined as a combination of moderate AS and moderate AI) and normal LVEF. 38% of patients had a bicuspid aortic valve. Adverse events were defined as NYHA class 3/4 symptoms, AVR, or cardiac death. Adverse events occurred in 77% of patients, including symptoms in 69%, AVR in 67% of patients, and cardiac death in 4% of patients. When compared with age- and sex-matched isolated moderate AI, moderate AS, and severe AS groups, adverse event rates in the moderate MAVD group were similar to that of the isolated severe AS group (71% for the moderate MAVD group vs 68% for the isolated severe AS group) and significantly higher than the isolated moderate AS or isolated moderate AI groups. Thus, the authors conclude that patients with moderate MAVD should be monitored similarly to patients with isolated severe AS.

Isaza et al. 202018: 862 patients with normal LVEF and at least moderate AI and moderate AS. Within this cohort, the average mean gradient was 36 mmHg, and 78% of patients had moderate AI compared to 22% of patients with severe AI. At 4.6 years, 59% of patients underwent an AVR, and 49% of patients died. AVR was associated with improved survival. The survival benefit of AVR existed regardless of aortic stenosis severity (AVA ≤1.0 cm2 vs AVA >1.0 cm2) or symptom status (NYHA 1 vs NYHA 2-4).

Saijo et al. 202119: This study aimed to understand the relationship between MAVD and LV global longitudinal strain (LV-GLS) and to assess the prognostic utility of LV-GLS in MAVD. 783 patients with LVEF ≥50% and MAVD (defined as coexisting at least moderate AS and at least moderate AI). 458 (59%) of patients underwent AVR at a median of 50 days. At a median follow-up of 5.6 years, 391 (50%) of patients had died. Patients with worse LV-GLS had worse outcomes, and LV-GLS was found to be associated with mortality in a linear relationship. Overall, LV-GLS may be useful for risk stratification in patients with MAVD.

Saijo et al. 202320: Retrospective review of 489 patients with MAVD (defined as coexisting at least moderate AS and at least moderate AI) with baseline LVEF ≥50% who underwent AVR. AVR in MAVD patients did not have a significant effect on LV systolic function quantified by LVEF and LV-GLS. During a median follow-up of 5.8 years, 65/134 (34%) patients with echocardiography follow-up had died. Patients with postoperative LVEF ≥50% had better survival, and within this group, mortality significantly differed by degree of LV-GLS. Notably, mean LV-GLS and LVEF in the postoperative setting remain similar to baseline. The authors conclude that worse postoperative LV-GLS and LVEF are both independently associated with increased mortality in MAVD.

Ongoing Trials/Recent Publications

The authors are not aware of any ongoing randomized clinical trials primarily focused on mixed aortic valve disease in the United States. However, the J-Valve Transfemoral Pivotal Study (JOURNEY, ClinicalTrials.gov ID: NCT06455787) assesses the safety and efficacy of the J-Valve Transfemoral (TF) System in patients with symptomatic, severe (grade 3 or 4), native aortic valve regurgitation (AR) and AR-dominant mixed aortic valve disease, who are judged by a multi-disciplinary heart team to be at high risk for open surgical aortic valve replacement (SAVR).

Expert Commentary

Patients who present with mixed aortic valve disease are more likely to become symptomatic with less than severe dysfunction, as their heart is under increased demand throughout the entire cardiac cycle. Many of these patients are relatively young, commonly have a bicuspid or unicuspid aortic valve, and may not recognize that they are having symptoms. It is important to intervene before irreversible cardiac remodeling occurs because doing so has been shown to improve survival. Complex techniques of imaging analysis have provided novel measures of remodeling that correlate with survival. These parameters can refine decision-making and guide more precise decisions about the timing of intervention. When aortic valve repair and replacement can be performed safely (<1% mortality) and effectively (without patient prosthesis mismatch), it is important to perform the operations prior to the onset of advanced remodeling.

Sources

  1. Otto CM, Nishimura RA, Bonow RO, 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 [published correction appears in Circulation. 2021 Feb 2;143(5):e228. doi: 10.1161/CIR.0000000000000960.] [published correction appears in Circulation. 2021 Mar 9;143(10):e784. doi: 10.1161/CIR.0000000000000966.]. Circulation. 2021;143(5):e35-e71. doi:10.1161/CIR.0000000000000932
  2. Nedadur R, Belzile D, Farrell A, Tsang W. Mixed aortic stenosis and regurgitation: a clinical conundrum. Heart. 2023;109(4):264-275. Published 2023 Jan 27. doi:10.1136/heartjnl-2021-320501
  3. Unger, P., & Clavel, M. A. (2020). Mixed Aortic Valve Disease: A Diagnostic Challenge, a Prognostic Threat. Structural Heart, 4(6), 468–474. https://doi.org/10.1080/24748706.2020.1817643
  4. Akintoye E, El Dahdah J, Dabbagh MM, et al. Longitudinal Assessment of Left Atrial Remodeling in Patients With Chronic Severe Aortic Regurgitation. JACC Cardiovasc Imaging. 2024;17(10):1133-1145. doi:10.1016/j.jcmg.2024.04.007
  5. Roselli EE, Abdel Azim A, Houghtaling PL, Jaber WA, Blackstone EH. Pulmonary hypertension is associated with worse early and late outcomes after aortic valve replacement: implications for transcatheter aortic valve replacement. J Thorac Cardiovasc Surg. 2012;144(5):1067-1074.e2. doi:10.1016/j.jtcvs.2012.08.029
  6. Beach JM, Mihaljevic T, Svensson LG, et al. Coronary artery disease and outcomes of aortic valve replacement for severe aortic stenosis. J Am Coll Cardiol. 2013;61(8):837-848. doi:10.1016/j.jacc.2012.10.049
  7. Beach JM, Mihaljevic T, Rajeswaran J, et al. Ventricular hypertrophy and left atrial dilatation persist and are associated with reduced survival after valve replacement for aortic stenosis. J Thorac Cardiovasc Surg. 2014;147(1):362-369.e8. doi:10.1016/j.jtcvs.2012.12.016
  8. Mihaljevic T, Nowicki ER, Rajeswaran J, et al. Survival after valve replacement for aortic stenosis: implications for decision making. J Thorac Cardiovasc Surg. 2008;135(6):1270-1279. doi:10.1016/j.jtcvs.2007.12.042
  9. Alashi A, Khullar T, Mentias A, et al. Long-Term Outcomes After Aortic Valve Surgery in Patients With Asymptomatic Chronic Aortic Regurgitation and Preserved LVEF: Impact of Baseline and Follow-Up Global Longitudinal Strain. JACC Cardiovasc Imaging. 2020;13(1 Pt 1):12-21. doi:10.1016/j.jcmg.2018.12.021
  10. Andell P, Li X, Martinsson A, et al. Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study. Heart. 2017;103(21):1696-1703. doi:10.1136/heartjnl-2016-310894
  11. Enriquez-Sarano M, Tajik AJ. Clinical practice. Aortic regurgitation. N Engl J Med. 2004;351(15):1539-1546. doi:10.1056/NEJMcp030912
  12. Rashedi N, Popović ZB, Stewart WJ, Marwick T. Outcomes of asymptomatic adults with combined aortic stenosis and regurgitation. J Am Soc Echocardiogr. 2014;27(8):829-837. doi:10.1016/j.echo.2014.04.013
  13. Honda S, Kitai T, Okada Y, et al. Impact of aortic regurgitation on the prognosis of severe aortic stenosis. Heart. 2012;98(21):1591-1594. doi:10.1136/heartjnl-2012-302089
  14. P Lupinek, M Kotrc, T Marek, R Kockova, V Pecenkova, Z Dorazilova, M Blaha, J Benes, A Praveckova, K Kroupova, V Capkova, M Podzimkova, J Kettner, J Kautzner, Moderate mixed aortic valve disease -evaluation, treatment and prognosis of patients referred to heart valve center, European Heart Journal, Volume 44, Issue Supplement_2, November 2023, ehad655.1733,
  15. Egbe AC, Poterucha JT, Warnes CA. Mixed aortic valve disease: midterm outcome and predictors of adverse events. Eur Heart J. 2016;37(34):2671-2678. doi:10.1093/eurheartj/ehw079
  16. Rosenhek R, Zilberszac R, Schemper M, et al. Natural history of very severe aortic stenosis. Circulation. 2010;121(1):151-156. doi:10.1161/CIRCULATIONAHA.109.894170
  17. Egbe AC, Luis SA, Padang R, Warnes CA. Outcomes in Moderate Mixed Aortic Valve Disease: Is it Time for a Paradigm Shift?. J Am Coll Cardiol. 2016;67(20):2321-2329. doi:10.1016/j.jacc.2016.03.509
  18. Isaza N, Desai MY, Kapadia SR, et al. Long-Term Outcomes in Patients With Mixed Aortic Valve Disease and Preserved Left Ventricular Ejection Fraction. J Am Heart Assoc. 2020;9(7):e014591. doi:10.1161/JAHA.119.014591
  19. Saijo Y, Isaza N, Conic JZ, et al. Left Ventricular Longitudinal Strain in Characterization and Outcome Assessment of Mixed Aortic Valve Disease Phenotypes. JACC Cardiovasc Imaging. 2021;14(7):1324-1334. doi:10.1016/j.jcmg.2021.01.020
  20. Saijo Y, Wang TKM, Isaza N, et al. Prognostic impact of left ventricular systolic dysfunction in patients with mixed aortic valve disease undergoing aortic valve replacement. Echocardiography. 2023;40(4):318-326. doi:10.1111/echo.15544
  21. Thourani VH, Brennan JM, Edelman JJ, et al. Association of Volume and Outcomes in 234 556 Patients Undergoing Surgical Aortic Valve Replacement. Ann Thorac Surg. 2022;114(4):1299-1306. doi:10.1016/j.athoracsur.2021.06.095
Previous Topic
Back to Lesson
Next Topic
error: Content is protected!