Natural History, Diagnostic Approaches, andTherapeutic Strategies for Patients With

Asymptomatic Severe Aortic Stenosis

Dr Siva SubramaniyanPGIMER &Dr.RML HospitalNew Delhi

INTRODUCTION

• Aortic stenosis is one of the most common forms of acquired valvular heart disease.

• The development of symptoms- syncope, angina,or heart failure, in patients with severe aortic stenosis predicts a high likelihood of mortality and Aortic valve replacement

• AVR is the only therapy to significantly improve both survival and symptoms.However the management of the asymptomatic patient is controversial.

• As the risk of sudden death in asymptomatic patients is relatively low, many advocate conservative management of these patients as the immediate risk of AVR may be higher.

• However, patients with asymptomatic severe AS are a heterogeneous group with some being at a much higher risk of sudden death than others,

• Over the past decades, several investigators have tried to establish which factors may help identify those patients at higher risk of sudden death.

• The vast majority of studies have used parameters identified by non-invasive imaging modalities.

• How these parameters may influence clinical practice and potentially identify patients that warrant early surgical intervention.

AS

definition of asymptomatic AS

NATURAL COURSE OF ASYMPTOMATIC SEVERE AS

progression of AS

• Patients with asymptomatic severe AS have a better prognosis than those with symptomatic severe AS.

• however, 5 years after receiving the diagnosis, approximately two thirds of conservatively managed patients with asymptomatic AS will develop symptoms, and 75% will have either died or undergone AVR

HEMODYNAMIC PROGRESSION

• The rate of hemodynamic progression of severe AS is variable and unpredictable.

- The average annual increase in aortic jet velocity has been estimated to be 0.3 m/s, and

- the annual decrease in AVA has been estimated at 0.1 cm2

• Several predictors of rapid hemodynamic progression have been reported, including smoking, dyslipidemia, male sex, diabetes mellitus, hypertension, chronic kidney disease, and coronary artery disease.

• The aortic valve calcium load is the most powerful predictor of rapid stenosis progression

• In patients with asymptomatic severe AS, 1-year and 5-year survival rates have been reported to range from 67% to 97% and 38% to 83%, respectively

Eur Heart J 2010;31:1390–7.

• A recent retrospective analysis of 1,517 conservatively treated patients with asymptomatic severe AS by Taniguchi et al., the largest study to date, reported 1-year and 5-year survival rates of 92.8% and 73.6%, respectively

J Am Coll Cardiol 2015;66:2827–38.

• Patients with limiting symptoms on exercise testing are significantly more likely to develop spontaneous symptoms or die than those without exercise-limiting symptoms

• Other reported predictors of death or subsequent need for AVR include age, chronic heart failure, chronic renal insufficiency, and inactivity

• Beta-blocker use and higher LVEF have been associated with better prognosis .

• Although statin use in patients with AS has been shown to decrease the rates of ischemic cardiovascular events (mainly the need for coronary artery bypass graft), its role in preventing major clinical valve-related outcomes (such as the need for AVR) has never been demonstrated

DEVELOPMENT OF SYMPTOMS AND THE NEED FOR AVR

• The median time to symptom onset, AVR, or death has ranged between 1 and 4 years.

• however, the definitions of what constitutes “symptoms” have differed across studies, and some studies reported only cardiac death and/or hospitalization, rather than death and/or symptom onset.

• Recently, 582 asymptomatic severe AS, by Taniguchi et al. reported the emergence of AS-related symptoms in 46.3% of patients undergoing medical observation compared with 3.2% for patients undergoing early AVR (p < 0.001) at a median follow-up of 1,361 days.

• Importantly, up to 19.9% in the observation group compared with 3.8% in the early AVR cohort were hospitalized for heart failure (p < 0.001).

• Also, among the 291 patients treated with the conservative approach, AVR was performed in 118 patients (41%) during follow-up, with a median interval of 780 days from diagnosis

• Hemodynamic severity of AS, the degree of aortic valve calcification, positive stress test results, and LV hypertrophy have been associated with more rapid symptom onset

SUDDEN DEATH IN ASYMPTOMATIC SEVERE AS

• The risk of sudden death has been reported to be approximately 1% per year in clinically asymptomatic patients with severe AS

• However, once symptoms occur, as many as 3% of patients may die suddenly within 3 to 6 months, and as many as 6.5% of symptomatic patients may die while awaiting AVR

DIAGNOSIS

• ECHO

• Stress evaluation

• CT

• MRI

• biomarkers

these investigation mainly used for prognostic purpose and which patient require AVR vs conservative management

ECHOCARDIOGRAPHY

• Two-dimensional/Doppler echocardiography plays a fundamental role in the diagnosis of AS.

• It is important to examine the etiology of AS, visual severity of valve calcification, position of the coronary artery orifice, concomitant myocardial disease, wall motion asynergy, and other valvular heart diseases

• An important consideration in echocardiography is to detect the highest peak aortic flow velocity using multiple transducer positions (the suprasternal window and right parasternal window with right decubitus position should be used in addition to the apical window).

• Vmax is one of the strongest independent echocardiographic predictors of adverse cardiovascular events in patients with AS

• The pressure gradient is calculated according to the modified Bernoulli equation; the pressure gradient = 4 × ν2.

• AVA is calculated by a continuity equation. Measurement of the LVOT size for stroke volume calculation is the second possible error for diagnostic severity. ASE guidelines recommend the measurement at the same position of the pulse wave sample volume, specifically 0.5 to 1 cm below the aortic annulus.

• Accurate measurement of LVOT diameter is critical, as the continuity method requires squaring of this measurement. Even an error of a few millimetres in this measurement can lead to large differences in the severity

• AVA can also be measured by planimetry, both by transthoracic echocardiography and transesophageal echocardiography. The planimetry method has its own limitations. Shadowing by calcification interferes with the visualization of the valve edge.

• A low-dose dobutamine stress echocardiography is performed to diagnose true or pseudo AS in low-gradient, reduced EF patients.

• A maximum velocity ≥ 4.0 m/s with AVA ≤ 1.0 cm2 at any flow rate during dobutamine stress echocardiography is diagnosed as true severe AS

• Diastolic dysfunction is an important parameter in the evaluation of AS. It has been reported by Park et al that echocardiographic markers of diastolic dysfunction, such as increased E/e′ and left atrial volume index, are associated with dyspnea in severe AS patients.

• Increased E/e′ (> 15) has been shown to predict survival in both asymptomatic and symptomatic patients with AS.

• current guidelines do not support its use in surgical decision making in patients with either symptomatic or asymptomatic AS.

new parameters in ECHO

• Valvuloarterial impedance (Zva) and longitudinal strain are emerging as alternative markers for assessing AS on LV function

• Zva- is defined as the ratio of the LV systolic pressure to the stroke volume index

• Zva takes into account both the valvular load, which is determined by AS severity, and the arterial load, which is determined by reduced arterial compliance, and increased systemic valvular resistance.

• Higher Zva has been associated with major cardiovascular events and mortality in populations with asymptomatic AS ranging from mild to severe AS

• Hachicha et al. found that Zva was independently associated with mortality and Lancellotti et al. prospectively followed 163 patients with asymptomatic AS and an indexed AVA < 0.6 cm2/m2, and corroborated these findings by showing that Zva was independently associated with adverse cardiac events.

• Zva cutoff values ranging from 4.5 to 5.0 mm Hg/ml/m2 identify severely elevated global hemodynamic load and have been shown to predict subsequent death, AVR, and development of symptoms.

SPECKLE TRACKING

• Assessment of global longitudinal strain measures the impact of severe AS on theLV and is believed to reflect subendocardial cardiomyocyte dysfunction secondaryto concentric remodeling, subendocardial ischemia, and myocardial fibrosis.

• Up to 50% of patients with asymptomatic severe AS and preserved LVEF havesome degree of subclinical myocardial dysfunction, as documented by reducedlongitudinal strain

• Low longitudinal strain is an independent predictor of symptom development. Inpatients with asymptomatic severe AS and preserved LVEF, decreasedlongitudinal strain is associated with an abnormal response to exercise andhigher rates of cardiac events at follow-up.

STRESS EVALUATION

• for patients with asymptomatic severe AS undergoing stress testing, the incidence of abnormal stress test has ranged between 28% and 67%, with a pooled average of 49% .

• An abnormal response to exercise is thought to reflect poor contractile reserve and an increased transvalvular gradient and Zva during effort

• AVR is recommended (Class I if clear valve-related symptoms occurred during stress test) and may be reasonable (Class IIa for abnormal blood pressure response or poor exercise tolerance) for asymptomatic patients with severe AS by current AHA/ACC and ESC/European Association of Cardio-Thoracic Surgery (EACTS) guidelines

EXERCISE STRESS ECHO

• Emerging data suggest that exercise stress echo provides incremental prognostic information in severe asymptomatic aortic stenosis

• An exercise-induced increase in the AV gradient >20 mm Hg [Maréchaux S, 2012] or 18 mm Hg [Lancellotti P, 2005] predicts future cardiac events

• Increase in gradient reflects fixed valve stenosis with limited valve compliance

DSE

• Contractile reserve (CR) is defined as an ↑more than 20% in SV during low-dose DSE

• Pts with no CR have a high operative mortality rate during AVR; but treated conservatively (65%/5y), they have a much worse prognosis than AVR (11%/5y) [Tribouilloy C.JACC 2009:53]

• TAVI is an interesting alternative to surg AVR in this subset of patients [ClavelMA.Circ 2010:122]

CT• AV calcification is a prognostic factor in asymptomatic AS. Rosenhek et al

evaluated the degree of AVC using echocardiography and showed moderate and severe AVC related to future death or development of symptoms.

• However, the definition of the degree of AVC by echocardiography has not been established

• A cardiac CT scan can provide quantitative measure of AVC, and > 1000 Agastonunits can be considered severe calcification. Currently, a cardiac CT scan can be used as a complementary method for the diagnosis and management of AS.

• Due to the recent rapid development of TAVR procedures, the cardiac CT scan has emerged as a key imaging modality not only to assess aortic valve and root calcification, but also for precise measurement of the aortic annulus and peripheral arteries

MAGNETIC RESONANCE IMAGING

• MRI has the advantage of providing more accurate anatomical and hemodynamic information, LV mass, and stroke volume than echocardiography.

• In addition, cardiac MRI with gadolinium contrast can provide information about fibrosis or collagen deposition of the myocardium, which is a consequence of long-term exposure to substantial afterload. The presence or absence of myocardial fibrosis in any cardiac disease is an important prognostic factor

• Fibrosis indicate irreversible changes started and unlikely recover after AVR

• But prognostic studies linking fibrosis to outcomes, are warranted before MRI can be used in routine clinical practice for the management of patients with AS

Biomarkers in AS

• Brain natriuretic peptide (BNP) is thought to be a good marker of increased wall stress in the myocardium.

• Bergler-Klein et al reported that asymptomatic severe AS patients whose plasma BNP was < 130 pg/mL rarely developed symptoms for 6 to 9 mo.

• Another study showed that a BNP ≥ 300 pg/mL was a poor prognostic factor in medically followed severe AS patients who were both symptomatic and asymptomatic

• Disadvantages of BNP include that fact that it is not disease-specific, and BNP levels vary even in the same patient according to physical activities and loading conditions.

• Therefore, a single value of BNP may not be helpful in surgical decision making in asymptomatic severe AS patients.

• serial measures and rising levels of BNP can be used for surgical decision making in asymptomatic severe AS patients, as proposed by European Society of Cardiology (ESC) guidelines

MANAGEMENT

THERAPEUTIC STRATEGY

• Medical therapy

• Aortic valve replacement

MEDICAL THERAPY

• Despite the long clinical silent phase of AS, there is currently no treatment to prevent the progression of this disease and delay the need for AVR.

• Many attempts to demonstrate the benefit of different medical therapies failed to demonstrate clinical value.

• Indeed, statin therapy, despite histological and genomic evidence of the association of lipoproteins variant with aortic valve calcification, has repetitively failed to show any clinical benefits to halt AS progression

• current ACC/AHA guidelines do not recommend (Class III) statin therapy if AS is the only indication

• Whether other novel strategies targeting osteogenic and inflammatory pathways will result in meaningful clinical applications in the treatment of early stages of AS remains to be seen in larger prospective and randomized trials .

• on the basis of studies showing the benefit of optimal blood pressure control, especially when using drugs blocking the renin-angiotensin pathway , current guidelines do recommend the appropriate and optimal treatment of hypertension in patients with asymptomatic or symptomatic AS

conservative vs early AVR ?

why not AVR for all asym. AS

• Operative mortality is one of the most important determinants of earlyoperation. It has been reported that operative mortality of isolated AVR for AS is1–3% in patients younger than 70 years and 3–8% in older patients.

• In the early studies, operative mortality was much higher than the incidence ofsudden death

• Prosthetic valve-related morbidity and mortality have also decreased withimprovements in valve products

• improved surgical techniques have led to lower operative mortality. Also,operative mortality in patients who underwent early operation or inasymptomatic patients was lower than for those receiving conventional strategyor in symptomatic patients- so in future indication may widen to asymptomaticAS

AVR

ESC

• study by Taniguchi et al, early operation group included patients with very severe AS (n=118, 41%), with left ventricular dysfunction (n=19, 7%) and candidates for other cardiac surgeries (n=24, 8%), which are recommendations for AVR in the current guidelines.

• Therefore, it is difficult to conclude right now that early operation is recommended in every patient with asymptomatic severe AS other than current guideline recommendations. Risk stratification for asymptomatic severe AS is needed to select patients who may have greater benefit from early operation.

• There are no randomised studies comparing outcomes between conventional strategy and early operation. Randomised studies are absolutely necessary for demonstrating the benefit of early operation over watchful waiting strategy.

surgery or TAVI?

role of TAVI

• TAVI has emerged as an alternative treatment option for elderly patients considered at high or prohibitive operative risk due to comorbidities

• TAVI may have some impact in determining treatment strategy because it can be indicated for elderly patients at a high operative risk when symptoms develop.

• On the other hand, there is a possibility that the indications for TAVI might be extended to asymptomatic severe AS in future. Currently, TAVI is indicated in symptomatic severe AS with high operative risk

• However, studies regarding outcomes of TAVI for lower-risk patients have been reported and some trials are ongoing

• Because prosthesis–patient mismatch is an important issue in surgical AVR, TAVI may become the optimal choice for patients with asymptomatic severe AS with narrow annulus, which is often seen in elderly patients

SUMMARY

• Approximately one-half of patients diagnosed with severe AS do not report symptoms or vague symptoms

• Decisions for AVR are based on the presence or absence of symptoms, but proactive investigation with multimodality testing for risk assessment is recommended in patients who are asymptomatic or who have indeterminate symptoms

• Exercise stress testing is recommended for asymptomatic severe AS patients in addition to two-dimensional/Doppler echocardiographic testing at rest for risk stratification.

• If a patient is not physically appropriate for exercise testing, use of a biomarker and multiple imaging modalities, such as CT and MRI with contrast, can complement the risk stratification of asymptomatic severe AS.

• Given the uncertainty regarding the value of AVR in asymptomatic severe AS and the large number of affected patients, a randomized clinical trial comparing AVR (either surgical and/or transcatheter) to conservative treatment is warranted.

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