Stress Echo for Hemodynamics and Valve Disease
Stress Echocardiography in Valvular Heart Disease Dr Rajdeep S. Khattar DM FRCP FACC FESC
Department of Cardiology & Echocardiography Laboratory, Royal Brompton & Harefield NHS Trust, London, UK Biomedical Research Unit, National Heart and Lung Institute, Imperial College, London, UK
The pathophysiology of valvular heart disease has traditionally been assessed in the resting state by echocardiography. However, over the last two decades, the dynamic nature of valvular heart disease has become a recognised phenomenon. Symptoms due to valve disease are usually exertional in nature and so a disparity between resting evaluation of valve dysfunction and patient symptoms is not uncommon. Changes in loading conditions, heart rate and ventricular contractility that occur with exercise can alter the physiological effects of valvular stenosis and regurgitation. Consequently, stress echocardiography is emerging as a very important clinical tool for the evaluation of valvular pathology.
As a general rule, in the evaluation of valvular heart disease, stress echocardiography is performed using treadmill or supine bicycle exercise rather than pharmacological stressor agents such as dobutamine. Exercise stress allows a truly physiological assessment of the consequences of valvular lesions with clinically relevant information on functional capacity and correlation of echocardiographic findings with exercise-induced symptoms. The use of echocardiography under these conditions allows a full evaluation of the mechanistic changes in valvular and ventricular dynamics and function, along with a quantitative evaluation of forward output, retrograde flow and pulmonary artery pressure.
Asymptomatic severe aortic stenosis
The prognosis of patients with severe aortic stenosis (AS) becomes adversely affected once symptoms develop. Asymptomatic patients have a more favourable outcome with a less than 1% per year mortality. However, one third of presumed asymptomatic patients actually develop symptoms on exertion when objectively tested using exercise stress testing(ref 1). Recent studies of patients with asymptomatic severe AS undergoing exercise echocardiography have shown that the presence of a resting mean aortic valve (AV) gradient ≥ 35 mmHg or an increase in mean gradient by ≥18-20 mm Hg during exercise may be an independent predictor of cardiac events over and above the development of exercise-induced symptoms, fall in blood pressure or complex ventricular arrhythmias (ref 2). The reason for individual variations in the response to exercise may be related to differences in leaflet stiffness and therefore valve compliance, which is a measure of change in the effective orifice area of a valve in response to alterations in flow (7,8). Both the American Heart Association (AHA)/American College of Cardiology (ACC) and European Society of Cardiology (ESC) guidelines advocate the use of exercise testing in asymptomatic severe AS to unmask symptoms in patients who may have sedentary lifestyles (refs 3,4). The clinical use of exercise echocardiography is more difficult to establish due to limited data and the use of soft endpoints in prognostic studies. Nevertheless, it may be reasonable to use exercise echocardiography to risk stratify patients with asymptomatic severe AS and help identify those who might benefit from closer follow-up.
Low flow, low gradient aortic stenosis with LV dysfunction
Low-flow, low-gradient AS refers to patients with apparently severe AS (valve area < 1 cm2) but low mean AV gradient (<40mmHg) and impaired left ventricular (LV) systolic function (EF <40%). An echocardiographic long-axis parasternal view of a patient with this condition is shown in Video 1. This entity encompasses two distinct pathologies as follows: (i) those with truly severe AS leading to increased afterload, secondary LV dysfunction and inadequate driving forces through the valve leading to a reduction in the aortic valve gradient, and (ii) those with relative or pseudo-severe AS in whom although there is reduced opening of the aortic valve and a degree of stenosis, the primary pathology is myocardial disease causing the LV dysfunction leading to a reduced stroke volume and low AV gradient. In this instance, stress echocardiography with dobutamine is preferable to exercise to help distinguish between these groups and is recommended in international guidelines. The test examines whether there is LV contractile reserve and if present, whether this leads to a change in AV area and mean AV gradient (Figure 1). In patients with contractile reserve there should be an increase in trans-valvular flow and in those with truly severe AS this should lead to an increase in the mean gradient, but no change in the AV area. In patients with pseudo-severe AS, the AV area should increase and the mean gradient remain the same. The main limitation of this test is that in those without contractile reserve, it is not possible to differentiate between the two entities. Current, albeit, limited data suggest that in those undergoing aortic valve replacement (AVR), those with contractile reserve have a much lower peri-operative mortality than those without contractile reserve (5% versus 31%, respectively). However, AVR remains superior to medical therapy (ref 5) even in those without contractile reserve and therefore should still be considered a therapeutic option in these patients (Figure 2). Recent registry data in those with intrinsic myocardial disease and pseudo-severe AS, support the use of medical therapy in this group of patients (ref 6).
Chronic severe aortic regurgitation (AR) leads to progressive volume and pressure overload of the left ventricle. Current guidelines recommend AVR in symptomatic patients or in asymptomatic patients with LV dilatation or dysfunction (end-systolic diameter is >50mm (ESC) or >55mm (AHA/ACC) or EF <50% (9,10). Limited data on stress echocardiography in AR suggest that the lack of an increase in ejection fraction with exercise may predict LV dysfunction in both surgically and medically treated patients. Current international guidelines recommend exercise testing for objective evaluation of exercise capacity but do not advocate the use of exercise induced parameters of LV function in clinical practice (refs, 3,4).
Significant mitral stenosis (MS) causes an obstruction to LV inflow which results in an elevation of left atrial pressure, increased pulmonary venous pressure and eventually increasing pulmonary hypertension. A proportion of patients have significant exertional symptoms despite having MS, which is quantified as moderate at rest. Changes in LV haemodynamics during exercise including a reduced diastolic filling time or increased trans-mitral blood flow in the presence of a fixed stenosis may result in further increases in left atrial pressure and pulmonary venous pressure and thereby may cause symptoms of dyspnoea. A recent small study demonstrated the clinical utility of exercise echocardiography in patients with moderate MS and disproportionately severe symptoms (ref 7). The test was stopped because of dyspnoea in 35 patients (76%) all of whom developed a mean trans-mitral gradient of at least 15 mmHg or PA systolic pressure >60 mmHg. The reason for the variability in response to exercise may be due to a combination of mitral valve and left atrial compliance. The mitral valve area is dynamic and may increase during exercise. The degree of change in mitral valve area is mainly dependent on the extent of leaflet mobility, thickening and calcification. Left atrial compliance is inversely correlated with exercise PA systolic pressure and functional class. Therefore, low left atrial compliance may lead to an exercise-induced increase in PA systolic pressure and development of symptoms. Indeed left atrial compliance has been shown to predict the need for future mitral valve intervention in patients with moderate mitral stenosis at rest. The prognostic value of dobutamine stress echocardiography in MS has also been investigated showing that a mean MV gradient of at least 18 mmHg during stress may be a good predictor of subsequent outcome (ref 8). Howeve, this test should be reserved for those unable to exercise adequately. AHA/ACC guidelines recommend dobutamine or exercise stress echocardiography in patients who are symptomatic despite Doppler measurements which do not indicate significant MS. An increase in mean mitral gradient to ≥15mmHg or pulmonary artery systolic pressure to ≥ 60mmHg is considered a Class IIb indication for consideration of percutaneous mitral valvotomy (9).
Degenerative Mitral Regurgitation
Chronic severe degenerative MR causes LV volume overload and unless treated in a timely fashion, may lead to LV dilatation and dysfunction. Surgery is recommended in those with symptoms and in asymptomatic patients with a pre-operative end-systolic diameter >4.5cm, LVEF < 60%, recurrent atrial fibrillation or PA systolic pressure ˃50mmHg. Patients with mild mitral regurgitation may present with disproportionately severe symptoms of dyspnoea on exertion, but up to a third of these patients may develop severe MR on exercise. Therefore exercise echocardiography may be used to identify such patients. An example of a patient with dyspnoea on exertion who demonstrated worsening MR on exercise is shown in videos 2 and 3. Small studies in asymptomatic patients with moderate to severe degenerative MR, show that exercise echocardiography may identify worsening exercise-induced MR in up to a third of patients (ref 9) with lower symptom-free survival in those with a marked increase in regurgitant volume. Furthermore, exercise-induced pulmonary hypertension seems to be an adverse predictor of outcome with a 2 year survival of 35% compared to 75% in those without an increase in pulmonary artery pressure. Exercise echocardiography can also be used to identify the presence of LV contractile reserve. A lack of contractile reserve defined as less than 4% increase in ejection fraction after exercise is associated with the development of late LV dysfunction and post-operative morbidity and deterioration of LV function in medically treated patients. Therefore, the presence of a normal LVEF in patients with severe MR may be misleading as a proportion of patients already have sub-clinical myocardial dysfunction. Myocardial deformation imaging is a more sensitive and less load dependent marker of LV contractile function than LVEF. A recent study demonstrated that global longitudinal strain normalised for LV end systolic diameter at peak exertion was the best echocardiographic predictor of post-operative LVEF in patients with organic MR. Further studies performed with serial measures of contractile reserve are needed to identify the threshold for optimal timing of surgery in patients with preserved LVEF. Guidelines recognise the value of exercise testing in presumed asymptomatic patients to objectively evaluate exercise capacity (refs 3,4). Exercise echocardiography can be used to examine the dynamic severity of MR in patients whose symptoms are out of proportion to the degree of mitral valve disease. However, current guidelines do not recommend intervention in asymptomatic patients who develop severe MR with exercise. Larger outcome studies examining mortality and indices of LV performance are required. Nevertheless, these patients are at higher risk of developing symptoms and should undergo careful follow-up. In relation to the identification of exercise induced pulmonary hypertension in asymptomatic patients there is a divergence of expert opinion. The AHA/ACC suggest that it would be reasonable to consider mitral valve intervention in asymptomatic patients with severe MR and normal LV function who have PASP >50mmHg at rest or >60mmHg on exercise. However it is not an indication for intervention in the ESC guidelines.
Chronic ischaemic MR is a frequent complication of coronary artery disease. The mechanism of regurgitation relates to a combination of LV remodelling, displacement of papillary muscles and tethering of valve leaflets, which leads to a lack of complete apposition of mitral valve leaflets. The prognosis of patients with even mild ischaemic MR and LV dysfunction is poor and is independent of the degree of LV dysfunction. The utility of exercise echocardiography in ischaemic MR has been demonstrated in those patients who develop acute pulmonary oedema with no obvious cause. These patients may show a large increase in severity of MR on exertion coupled with an increase in PA systolic pressure, which may explain their symptoms. In a study examining the prognostic value of exercise-induced changes, a resting effective regurgitant orifice area > 20mm2 or increase in MR ERO >13mm2 was associated with significantly lower survival (59% and 66%, respectively) compared to those with mild MR or smaller increases in MR on exertion (ref 10). Other centres have confirmed these findings although only using qualitative assessment of MR (40). While an increase >13mm2 unmasks patients at high risk of morbidity and mortality the effect of intervention on these patients is not known. Exercise echocardiography can be important in determining the cause of symptoms in patients whose resting severity of MR is out of proportion to the level of dyspnoea. It also provides prognostic information, which may help risk stratify patients. Identifying patients who have dynamic worsening MR together with the underlying mechanism has the potential to influence revascularisation strategies and the need for concomitant mitral valve intervention.
Stress echocardiography in valvular heart disease can provide additional diagnostic information by allowing an assessment of the interaction between functional capacity, development of symptoms and valvular and ventricular dynamics. It may also have a prognostic role in refining risk stratification to aid management decisions. A summary of the current indications for stress echocardiography in valvular disease is provided in Table 1. Although the use of stress echocardiography is recognised in guidelines, recommendations are largely based on consensus rather than strong evidence. There is therefore an urgent need for large prospective randomized trials to assess the impact of stress echocardiographic parameters on outcomes.
1. Pellikka PA, Sarano ME, Nishimura RA, Malouf JF, Bailey KR, Scott CG, Barnes ME,Tajik AJ. Outcome of 622 adults with asymptomatic hemodynamically significant aortic stenosis during prolonged follow-up. Circulation 2005;111:3290–3295. 2. Lancelotti P, Lebois F, Simon M, Tombeux C, Chauvel C, Pierard LA. Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis. Circulation 2005;112:377–382 3. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O'Gara PT, O'Rourke RA, Otto CM, Shah PM, Shanewise JS;2006 Writing Committee Members; American College of Cardiology/American Heart Association Task Force. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines 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 (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:523-661. 4. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink A; Task Force on the Management of Valvular Hearth Disease of the European Society of Cardiology; ESC Committee for Practice Guidelines. Guidelines on the management of valvular heart disease: the task force on the management of valvular heart disease of the European Society of Cardiology. Eur Heart J 2007;28:230-268. 5. Monin JL, Quéré JP, Monchi M, Petit H, Baleynaud S, Chauvel C, Pop C, Ohlmann P, Lelguen C, Dehant P, Tribouilloy C, Guéret P. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multi-center study using dobutamine stress hemodynamics.Circulation 2003;108:319-324. 6. Fougères E, Tribouilloy C, Monchi M, Petit-Eisenmann H, Baleynaud S, Pasquet A, Chauvel C, Metz D, Adams C, Rusinaru D, Guéret P, Monin JL.Outcomes of pseudo-severe aortic stenosis under conservative treatment.Eur Heart J 2012 7. Leavitt JI, Coats MH, Falk RH. Effects of exercise on transmitral gradient and pulmonary artery pressure in patients with mitral stenosis or a prosthetic mitral valve: a Doppler echocardiographic study. J Am CollCardiol 1991;17:1520–6. 8. Reis G, Motta MS, Barbosa MM, Esteves WA, Souza SF, Bocchi EA. Dobutamine stress echocardiography for noninvasive assessment and risk stratification of patients with rheumatic mitral stenosis. J Am CollCardiol 2004;43:393–401. 9. Magne J, Lancellotti P, PiérardLA . Exercise-Induced Changes in Degenerative Mitral Regurgitation. J Am CollCardiol 2010;56:300–309. 10. Lancellotti P, Troisfontaines P, Toussaint AC, Pierard LA. Prognostic importance of exercise-induced changes in mitral regurgitation in patients with chronic ischemic left ventricular dysfunction. Circulation2003;108:1713–1717.