Care of Patients With Apparently Asymptomatic Severe Aortic Valve Stenosis

Authors

  • Mary Ann Williamson MD,

    Corresponding author
    1. Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
    • Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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  • Eli V. Gelfand MD

    1. Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
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Abstract

Although most asymptomatic patients with aortic stenosis (AS) have an excellent prognosis with observation only, some patients with severely stenotic aortic valves in the absence of symptoms may benefit from early intervention. In this article, we will review the literature on the use of varied imaging modalities, clinical factors, and biomarker testing to risk stratify such patients. Additionally, we will review the role of medical therapy to modify the course in AS. Clin. Cardiol. 2012 DOI: 10.1002/clc.22072

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Aortic stenosis (AS) is the most common degenerative valvular lesion and the leading indication for valvular surgery in the developed world. It affects 2% of patients by the age of 65 years and 4% by the age of 85 years,1 with rising prevalence paralleling the aging population. Progressive AS leads to pressure overload of the left ventricle and eventually manifests with a variable combination of exercise intolerance, anginal chest discomfort, exertion-related syncope, congestive heart failure, or less commonly, sudden cardiac death.

The generally undisputed paradigm of the last 4 decades was that patients asymptomatic in daily life are at a negligible risk of sudden death and that reassurance combined with close clinical observation are sufficient. Indeed, the latest American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend surgery for asymptomatic patients with critical aortic stenosis (<0.6 cm2) only as a class IIb indication. On the other hand, the prognosis of untreated patients with limiting symptoms is poor, and thus aortic valve replacement (AVR) is uniformly suggested. In recent years, important diagnostic and therapeutic developments have created a more nuanced overall landscape of aortic stenosis management. These include:

  • New insights into biology of AS development and progression.

  • Recognition that many patients previously assigned to the asymptomatic group have significant “silent” limitations to their cardiopulmonary reserve.

  • Evidence that in some asymptomatic AS patients there is already evidence of myocardial damage prior to valve replacement.

  • Improvements in standard AVR techniques with resultant lower mortality and morbidity.

  • Development of percutaneous (transcatheter) AVR techniques.

New Insights Into the Biology of AS and Its Effects on the Myocardium

AS was long thought to be a passive process in the elderly. However, recent data have highlighted that AS is a biologically active, progressive disease beginning with mild sclerotic changes and culminating in a severely calcified dysfunctional valve. Early valvular lesions demonstrate the presence of chronic inflammatory cells, specifically activated macrophages and lymphocytes, along with oxidized lipoproteins, which stimulate further inflammation and mineralization. More advanced lesions show cells with osteoblastic capabilities and mature lamellar bone. In advanced lesions, angiotensin II type I and II receptors have been identified, leading to the hypothesis that this signaling process is involved in disease progression.2,3

Predictors of Clinical Outcomes in Asymptomatic AS Patients

Rates of AS progression vary greatly. An ability to better predict the rate of patient-specific AS progression and the likelihood of symptom development would presumably aid both the patient and the clinician in terms of planning the safest and most effective intervention. It may also reduce the risk of unexpected complications. In an effort to identify such predictors in asymptomatic patients, imaging parameters, exercise tolerance testing, and cardiac biomarkers have been studied. The results of relevant investigations are discussed below as well as summarized in Table 1.

Table 1. Predictors of Poor Outcomes in Asymptomatic Aortic Stenosis and Normal Left Ventricular Function
AuthorYearNo. of PatientsAssessment ToolOutcomeIndependent Predictors of Outcome
  1. Abbreviations: AVA, aortic valve area; AVR, aortic valve replacement; BNP, brain natriuretic peptide; CAD, coronary artery disease; CMR, cardiovascular magnetic resonance; CHF, congestive heart failure; ETT, exercise tolerance testing; LGE, late gadolinium enhancement; LV, left ventricular; NT-pro-BNP, N-terminal pro-BNP; OR, odds ratio; RR, relative risk; SCD, sudden cardiac death; TTE, transthoracic echocardiogram.

Otto et al51997123TTE  
Rosenhek et al62000128TTE59 AVR, 8 death, 6/8 cardiac SCDAortic valve calcium score 3 or 4
Amato et al11200166TTE and ETT34 symptoms, 4 SCDAVA <0.7 cm2, abnormal ETT
Rosenhek et al72004176TTE and patient/physician interview33 AVR, 34 death, 15/34 cardiac deathsAortic valve calcium score 3 or 4 RR 2.0,
     Aortic peak velocity of ≥3 RR 1.6, concomitant CAD RR 1.7
Das et al122005125TTE and ETT36 symptoms, 0 deathsSymptoms during ETT (OR 7.73)
Lancellotti et al14200569TTE at rest and exercise2 symptoms, 2 CHF requiring hospitalization, 12 AVR, 3 deathsExercised-induced increase in mean gradient ≥18 mm Hg, abnormal ETT, AVA <0.75 cm2
    2/3 SCD 
Gerber et al24200529NT-pro-BNP8 symptomsNT-pro-BNP of >50 pmol/L,
     OR = 13
Monin et al82009107TTE, ETT, and BNP58 AVR (dictated by symptoms or a positive ETT), 1 refused AVR but had symptoms, 3 deathsFemale sex, serum BNP, and peak aortic jet velocity at baseline
Lacellotti et al232010126TTE, BNP, and ETT48 AVR, 6 deaths, 3/6 SCD, 8 symptomatic refusing surgeryFemale, elevated BNP, left atrial area, late diastolic annular velocity, E/Ea ratio
Marechaux et al152010135TTE at rest and exercise in patients with normal ETT58 AVR, 2 cardiovascular deathsOlder age, diabetes, resting mean gradient >35 mm Hg, exercised induced increase in gradient by >20 mm Hg
Lancellotti et al352010163TTE, ETT, and systemic arterial hemodynamics and global LV after load57 AVR, 11 symptoms without AVR,Valvulo-arterial impedance, peak aortic jet velocity, LV longitudinal myocardial deformation, and left atrial area
    6 death, 3/6 SCD 
Cioffi et al362011209TTE72 AVR, 13 heart failure hospitalizations, 2 myocardial infarctions, 20 deaths, 16/20 cardiac, 1/16 SCDInappropriately high LV mass, diabetes, aortic valve calcium score 4, higher peak gradient
Dweck et al192011143CMR imaging with LGEAll-cause mortality, cardiac mortality, need for AVRLV midwall fibrosis

Echocardiography

The initial tool in evaluating AS is transthoracic echocardiogram (TTE). The most important prognosticator for development of symptoms is the degree of stenosis as determined by the physiologic valve area, which considers the current hemodynamic profile of the subject and should be indexed for the subject's size.4 Additional parameters seen on TTE can be useful in predicting disease course. Multiple studies have shown peak aortic jet velocity (Vmax) to predict events—surgery or death in patients with severe aortic stenosis.5–8 In 2010, a study showed that a Vmax >5.5 m/s showed event rates of 56% at 1 year and 89% at 3 years. Additionally, in this prospective study, severe AS was only a marker of outcome when Vmax was included in the analysis.9 In 2000, a prospective study of 128 subjects with severe AS and a Vmax of at least 5 m/s showed that, in those with moderate to severe valvular calcification, only 60% were free from events (development of symptoms or need for surgery) at 1 year and only 20% at 4 years. A 0.3 m/s increase in Vmax in 1 year did not prove to be an independent predictor but was an important marker when seen in patients with significant calcification. Of subjects with both markers (an increase in Vmax with moderate to severe calcification), 79% had an event within 2 years.6

In summary, peak transaortic velocity of >5.5 m/s and severe valve calcification with a >0.3 m/s annual increase in peak velocity identify patients at a high risk for symptom development and need for surgery.

Exercise Tolerance Testing

Exercise tolerance testing (ETT) in patients with frankly symptomatic AS patients is generally contraindicated. However, symptom-limited ETT provides useful prognostic information in selected asymptomatic patients. A recent meta-analysis of almost 500 asymptomatic patients with severe AS suggested no major complications from stress testing when proper supervision was provided.10 The general criteria for ETT “positivity” are different than those used in diagnosis of coronary artery disease and are listed in Table 2. In particular, exercise-induced ST-segment changes are common in patients with AS and have a low specificity for diagnosis of coronary artery disease (CAD). Amato et al demonstrated a significantly lower 2-year event-free survival in a group of 66 patients with severe AS among those with an abnormal ETT (19% vs 85% in subjects with a normal ETT).11 Importantly, additional studies have suggested that specific abnormal findings may be more reliable in predicting disease course than others, which is also supported in the guidelines (Table 3).12 The most consistent marker may be that of exercise-limiting symptoms, particularly in patients under the age of 70 years.13 Addition of echocardiography to ETT to evaluate for an increase in mean gradient during exercise may add value in prognosticating the disease course, even among patients with an otherwise normal ETT.14,15

Table 2. High-Risk Exercise Stress Test Findings in Patients With Severe Asymptomatic Aortic Stenosis
Induced fatigue and breathlessness at a low workload
Failure to raise systolic blood pressure >20 mm Hg
Chest pain, dizziness, or syncope at <4 METs of effort
Significant ST-segment depression
Induced complex ventricular arrhythmia
Table 3. Guidelines for AVR in Asymptomatic AS
 European Society of Cardiology16ACC/AHA17
  1. Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; AS, aortic stenosis; AVR, aortic valve replacement; CABG, coronary artery bypass graft; CAD, coronary artery disease; LV, left ventricular; LVEF, left ventricular ejection fraction; LVH, Left ventricular hypertrophy; N/A, not applicable.

Severe AS with LVEF <50%ICIC
Low gradient (<40 mm Hg) and LV dysfunction with contractile reserveIIaCClear benefit from AVR
Low gradient (<40 mm Hg) and LV dysfunction without contractile reserveIIbCCase by case as no level of evidence to identify who in this group will benefit
Need for CABG, ascending aorta surgery or repair of another valveIC (if severe), IIaC (if moderate)IC (if severe), IIa (if moderate), IIbC (if mild and evidence of possible rapid progression)
Abnormal exercise testing due to provocation of symptomsICIIbC
Abnormal exercise testing due to abnormal blood pressure response to exerciseIIaCIIbC
Abnormal exercise testing due to induction of ventricular arrhythmiasIIbCN/A
Severe AS with moderate to severe aortic valve calcification, CAD, and ageN/AIIbC
Severe AS with moderate to severe aortic valve calcification and rapid progression of peak velocity (≥0.3 m/s per year)IIaCN/A
Severe AS and excessive LVH (>15 mm) in the absence of hypertensionIIbCN/A
Severe AS and surgery may be delayed at onset of symptomsN/AIIbC

In summary, stress testing in patients with asymptomatic AS is both safe and instructive. It provides additional prognostic information not otherwise recognized in the resting state and has been incorporated into both European Society of Cardiology and ACC/AHA guidelines.13,16,17

Advanced Cardiac Imaging

Cardiovascular Magnetic Resonance Imaging: Cardiovascular magnetic resonance (CMR) imaging is now accepted as a reasonable approach in evaluating AS. Importantly, it offers information not available with traditional transthoracic echocardiographic approaches. First, it allows for direct measurement of the orifice area, aiding in cases with concomitant aortic regurgitation or left ventricular outflow obstruction, where Doppler assessment of the stenosis severity is less reliable. Second, precise anatomic assessment of the aortic root, ascending and descending aorta, can be accomplished18; this is important in cases where concomitant aortic surgery is considered. Third, CMR imaging allows for identification of myocardial fibrosis. Recent data suggest that the presence of midwall left ventricular (LV) wall fibrosis, as seen by late gadolinium enhancement (LGE), may portend a poor prognosis in patients with AS. All-cause mortality in such patients increases concurrently with the percentage of fibrosis of the total LV mass. Interestingly, although these subjects appear to have a higher mortality when undergoing aortic valve replacement, the overall increased mortality risk is eventually modulated by AVR.19

Cardiac Computed Tomography: Cardiac computed tomography (CCT) is an excellent method for evaluating aortic valve calcifications. A software package typically used to obtain coronary calcium (Agatston) score can be used to calculate an analogous “aortic valve calcium score” (AVC). Specifically, AVC has been shown to be an independent predictor of event-free survival in subjects with an aortic valve area <1.5 cm2 in prospective 5-year follow-up.20,21 A special niche for a 1-time CCT scan may eventually be exclusion of concomitant CAD in patients planned for AVR. Overall, the role of CCT in evaluating patients with AS is limited by its use of ionizing radiation, a significant concern in a population where serial testing is frequently needed.

Cardiac Biomarkers

Progression of AS is accompanied by LV pressure overload and increased myocardial wall stress. Elevated levels of brain natriuretic peptide (BNP) and its precursors, such as N-terminal pro-BNP (NT-pro-BNP), in some patients are therefore not surprising.22 Several observational studies demonstrate that asymptomatic severe AS patients with a baseline elevated NT-pro-BNP (>50 pmol/L) and BNP (>61 pg/mL) have a higher rate of developing symptoms over 12 to 18 months of follow-up.23,24

Medical Therapy in Aortic Stenosis

Recent advances in our understanding of pathobiology of degenerative aortic stenosis suggest a possible role for targeted medical therapies to halt disease progression. Unfortunately, the efficacy of those medical approaches tested rigorously in randomized clinical trials has been mixed at best.

Therapy with 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) was retrospectively seen to delay AS progression. Initial reports suggested a 45% reduction in the rate of progression among patients with mild to moderate AS in a cohort who were taking the drugs for dyslipidemia.25 The benefit was independent of total cholesterol and low-density lipoprotein levels, suggesting a possible pleotropic effect of statin therapy.26 Prospective trials have been less uniform in their findings. The Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression Study (SALTIRE) was a double-blinded placebo-controlled trial looking at the ability of statins to delay the progression of AS, as measured by aortic jet velocity and aortic valve calcium score. After 25 months of follow-up, the study found no difference in progression of AS. Several limitations of this study were the inclusion of patients with severe disease and lack of patients with mild disease, given that some of the benefit is thought to be in treating the disease at the early stages.27 The rosuvastatin Affecting Aortic Valve Endothelium to Slow the Progression of Aortic Stenosis (RAAVE) trial prospectively enrolled 121 patients with moderate to severe AS (aortic valve area, 1.0 cm2; mean age, 73.7 ± 8.9 years; 57 male and 64 female). The study showed that after 18 months of follow-up, the rate of AS progression based on aortic valve area was 0.05 cm2 compared to a rate of 0.1 cm2 in the control group (P = 0.041).28 This was the first prospective trial to show a true effect on delaying disease progression. The results of 2 large randomized controlled studies, the Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial and the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial, both failed to show a benefit of statins in patients without another indication for treatment.29,30 Overall, the trial data suggest that there is currently no definite indications for statin therapy in patients with aortic stenosis and normal serum lipid levels.

Safety of therapy with angiotensin-converting enzyme inhibitors (ACEI) in AS was studied in the Symptomatic Cardiac Obstruction-Pilot Study of Enalapril in Aortic Stenosis (SCOPE-AS) trial. The study demonstrated safety in a high-risk group of symptomatic patients with severe aortic stenosis.31 Efficacy of ACEI therapy is less apparent and has not been examined prospectively, but retrospective analyses suggest a lower all-cause mortality and smaller number of cardiovascular events.32 These salutary effects may be mediated by the renal and vascular benefits of ACEIs, as it appears unlikely that ACEI therapy results in clinically meaningful change in valve hemodynamics itself.33

Exploiting the fact that calcified aortic valves have markers of bone turnover, the bisphosphonates are now being studied for their potential to modify AS. Two recent very small retrospective studies have shown promising results in delaying the loss of valve area among small groups of patients on bisphosphonate therapy. However, randomized controlled studies are needed to demonstrate a real cause and effect relationship between bisphosphonate therapy and outcomes.1,34

Our Approach to Patients With Apparently Asymptomatic AS

The primary prognosticator among patients with AS is still the development of symptoms. Therefore, our approach still centers around a thorough initial and interval history, with emphasis on longitudinal changes in exercise tolerance and symptoms of chest discomfort, dyspnea, exercise-induced syncope, or heart failure. Involvement of close family members, if available, is often invaluable, as insidious symptoms are often better appreciated by external observers. We repeat echocardiography annually to assess the rate of progression of AS, identify patients with extremely high transvalvular peak velocity (>5.5 m/s), and to ensure that any asymptomatic decline in LV systolic function is registered early. In patients who are physically active, subjectively assessed as daily exercise tolerance of >4 metabolic equivalent tasks (METs), we do not routinely pursue stress testing. In asymptomatic but sedentary patients, exercise testing is performed under close supervision of a clinical physiologist, experienced in testing of patients with advanced cardiac disease. We strongly consider a surgical referral in patients who develop symptoms at a functional load of 4 METs or less, in those who develop sustained ventricular tachyarrhythmia, or have a flat or frankly hypotensive blood pressure response to exercise. We also typically perform annual plasma BNP testing. Although an isolated elevated BNP does not trigger a surgical referral, it serves as a useful inexpensive flag for identifying a higher-risk cohort of asymptomatic patients, for whom earlier reassessment should be considered. In very selected patients, primarily those with a small LV cavity and functional left ventricular outflow tract obstruction, we obtain a magnetic resonance scan to separate the degree of left-sided obstruction at each level. Although intriguing, we do not find that the routine CMR evaluation of AS patients for myocardial fibrosis offers any additional management guidance at this time.

In terms of medical management, based primarily on the previously described retrospective data, we often have a lower threshold for starting statins in patients with mild or moderate AS and another indication for such therapy. Likewise, we feel reassured that in the absence of hypotension, separately indicated ACEI therapy in patients with severe AS is safe. Bisphosphonates offer promise for a potential disease-modifying agent, but not enough evidence exists at this time for us to recommend their routine use.

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