Low Gradient, Low Ejection Fraction Aortic Stenosis John Chambers, MD

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1 Low Gradient, Low Ejection Fraction Aortic Stenosis John Chambers, MD Address Cardiothoracic Centre, St. Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK. Current Treatment Options in Cardiovascular Medicine 2003, 5: Current Science Inc. ISSN Copyright 2003 by Current Science Inc. Opinion statement Low gradient aortic stenosis can be caused by critical aortic stenosis causing left ventricular impairment or by more moderate aortic stenosis coexisting with another cause of left ventricular impairment. The main challenges are to differentiate these two states and then to determine whether the left ventricle is likely to recover after aortic valve surgery. Exhaustive echocardiography is necessary, including the use of dobutamine stress. Guideline criteria for severe aortic stenosis are given in this article. The most secure criteria are mean transaortic pressure difference greater than 30 mm Hg and effective orifice area less than 1.2 cm 2 during dobutamine stress. However, the presence of left ventricular contractile reserve more closely determines outcome after surgery than do markers of stenosis. Surgery is most clearly indicated if there is severe aortic stenosis and an increase in the systolic velocity integral by greater than 20% during dobutamine infusion. Preoperative catheterization is necessary to determine coronary anatomy, but the aortic valve should not be crossed because of the relatively high risk of death, stroke, pulmonary edema, and cardiogenic shock. In patients judged too ill for immediate surgery, a period of medical resuscitation with diuretics and dobutamine should be considered. Balloon valvotomy is not indicated. Introduction Aortic stenosis is common. Over the age of 75, about 3% of all people have severe aortic stenosis [1]. There is a long, asymptomatic latent-phase during which the risk of sudden death is low. However, the mortality rises sharply if there is exertional chest pain, syncope, or breathlessness [2]. Ideally, aortic stenosis should be detected in the asymptomatic phase as a result of auscultation during routine medical screening so that the patient can be observed carefully. Surgery is then indicated immediately upon development of exertional breathlessness or chest tightness [3]. However, we now realize that there is a mortality of up to 12% soon after the onset of symptoms or if there is a waiting list for surgery [4]. For this reason, modified Bruce treadmill exercise is increasingly being advocated to uncover symptoms in people who are sedentary, stoic, or imperfect historians [4,5]. The long-term outlook is excellent for patients having elective surgery [6]. However, for about 5% of patients having surgery, the initial presentation is with heart failure and recovery is less certain [7]. Their management remains difficult because there are two clinical situations that are difficult to differentiate. These include 1) severe aortic stenosis with secondary left ventricular impairment as a result of myocardial fibrosis, and 2) more moderate aortic stenosis coexisting with another cause of left ventricular impairment such as coronary disease, alcohol, or a cardiomyopathy. If the left ventricle is poor it may not provide the energy to open even a moderately stenotic valve. The effective orifice area may, therefore, be disproportionately low. The main aim of this article is to discuss how these clinical situations are differentiated. To do this it is necessary to consider the pathophysiology of the left ventricle in aortic stenosis. PATHOPHYSIOLOGY The left ventricle responds to pressure load in aortic stenosis by myocardial hypertrophy, which is thought to

2 470 Valvular, Myocardial, Pericardial, and Cardiopulmonary Disease Table 1. Guidelines to severe aortic stenosis in patients with low gradient, low ejection fraction aortic stenosis Peak transaortic velocity at rest, m/s > 3.5 Mean gradient at rest or during dobutamine infusion, mm Hg > 30 Peak to mean gradient at rest < 1.5 Resistance at rest, dynes/s/cm -5 > 200 Effective orifice area during dobutamine infusion, cm 2 < 1.2 Pressure drop flow slope with dobutamine, mm Hg/mL/s -1 > 0.1 Tei index at rest > 0.42 Relative prolongation of the ejection time at rest, ms > 70 limit wall stress and preserve systolic function [8]. However, ultimately, severe afterload causes a fall in left ventricular ejection fraction even in the presence of relatively preserved contractility. The available energy is used in overcoming the resistance to flow across the aortic valve with little remaining to expel blood into the aorta. Correction of this abnormally elevated afterload by aortic valve surgery allows the left ventricle to recover. In patients with a low ejection fraction, but preserved left ventricular contractility, the mean transaortic pressure difference falls. However, it usually stays above 30 mm Hg, which is approximately equivalent to a peak velocity of 3.5 m/s on continuous-wave Doppler. Low gradient, low ejection fraction aortic stenosis has been defined in a variety of ways. The mean transaortic pressure difference is taken variously as less than 30 mm Hg [9], less than 35 mm Hg [10,11], and less than 40 mm Hg [12,13], but the most inclusive threshold based on outcome data and surgical observation is less than 30 mm Hg [7,13]. Usually an effective orifice area less than 0.8 cm 2 is part of the definition, but more recently the threshold for significant stenosis has tended to rise to less than 1.0 cm 2 [3,12,13]. Using the higher threshold makes it less likely to miss severe aortic stenosis in larger patients because the clinical significance of an orifice area depends on body habitus. A reasonable definition of low gradient, low ejection fraction aortic stenosis is, therefore, a combination of all three of the following: left ventricular ejection fraction less than 40%; mean transaortic pressure difference less than 30 mm Hg; and effective orifice area by the continuity equation less than 1.0 cm 2. In this group surgical mortality is high, about 50%, compared with 8% for patients with a mean pressure difference above 30 mm Hg [7]. HOSPITALIZATION Patients with low ejection fraction aortic stenosis may present acutely with heart failure or may consult a general practitioner with progressive exertional breathlessness. The diagnosis may occasionally be missed because the ejection systolic murmur of aortic stenosis becomes softer as the cardiac output falls. It is vital that any patient with clinical heart failure in whom the etiology is not certain has an echocardiogram before starting treatment with diuretics and angiotensinconverting enzyme inhibitors. Once the diagnosis is made, the patient with low ejection fraction aortic stenosis must have an opinion from a cardiologist specializing in valve disease without delay. The median survival in such patients is only 12 months [2], so the best option is to admit immediately for inpatient investigation and treatment. The diagnostic aims in such patients are to 1)differentiate patients with severe from more moderate stenosis, and 2)determine if the left ventricle is likely to recover after aortic valve surgery. These can be approached by additional calculations at rest, but it is also almost always necessary to study the effect of dobutamine infusion (Table 1). INVESTIGATION Measures at rest Effective orifice area calculated using the continuity equation is relatively independent of flow and is widely used for the assessment of aortic stenosis, in addition to raw peak transaortic velocity and mean or peak pressure difference derived using the modified Bernoulli theorem. However, the continuity equation may be misleading in very low flow states when there is insufficient energy to open a mildly or moderately stenotic valve to its maximum extent. In this situation, there is evidence that waveform shape and the transaortic resistance, which is the ratio of mean pressure difference over flow, may be useful. As aortic stenosis progresses, the left ventricular ejection time and the time to peak velocity both lengthen [14]. This makes the waveform shape relatively broad and symmetrical. This shape is maintained even when the peak velocity falls as left ventricular dysfunction develops. By contrast, more moderate aortic stenosis is associated with a ski slope shaped signal. The difference in these shapes is reflected by the ratio of the peak to the mean pressure difference. If this is less than 1.5, it is likely that the aortic stenosis is severe [15]. With primary left ventricular dysfunction, the left ventricular ejection time is short [16]. However, with a combination of severe aortic stenosis and reduced left ventricular ejection fraction, the relative ejection time

3 Low Gradient, Low Ejection Fraction Aortic Stenosis Chambers 471 remains prolonged [15]. The relative ejection time (in seconds) can be calculated from the following formula [14]: stroke volume (in ml) If the observed ejection time is more than 70 ms longer than expected from the left ventricular ejection fraction, it is likely that the aortic stenosis is severe [14,15]. However, this calculation is relatively involved and the Tei index is easier and gives similar information. The Tei index is calculated as the following: (IVRT + ICT + EJT)/EJT where IVRT and ICT are isovolumic relaxation and contraction times and EJT is ejection time. A Tei index greater than 0.42 has been reported to differentiate almost all patients with severe aortic stenosis and left ventricular dysfunction from control subjects, or patients with aortic stenosis and preserved left ventricles [17]. Resistance is the simple ratio of mean pressure difference over flow and is calculated echocardiographically as the following: Resistance (in dynes.s.cm -5 ) = [1.333 mean pressure gradient (mm Hg) systolic ejection time (ms)]/stroke volume (ml). Resistance may be more sensitive than effective orifice area because there is a curvilinear relationship between the two quantities, with resistance changing more at the border between moderate and severe stenosis. Furthermore, although both are calculated using similar waveforms, the calculation required for resistance incorporates the ejection time, which, as discussed above, independently reflects the grade of aortic stenosis. Furthermore, ejection time and mean pressure drop are relatively easily measured and accurate, whereas there are errors associated with the positioning of the pulsed Doppler sample within the subaortic region and in the measurement of left ventricular outflow tract diameter. The potential benefit of resistance was shown by Cannon et al. [10]. These authors studied patients with low flow aortic stenosis and effective orifice area less than 0.6 cm 2. These were divided into those with genuinely critical stenosis usually confirmed by surgical inspection and those that were less severe. These two groups were reliably differentiated by a resistance over 200 dynes.s.cm -5. However, there has been uncertainty about resistance because most authors assume that pressure drop should be related to the square of flow as in the Gorlin relationship, whereas for resistance the pressure drop must be directly related to flow. In fact, in vivo at physiologic flows it is easier to draw a line than a curve through a plot of mean pressure drop against flow [18] derived using dobutamine stress echocardiography. However, the slope of the plot of pressure drop against flow varies so that resistance calculated at rest does not necessarily predict peak pressure difference during dobutamine stress [18]. Furthermore, a number of authors have found that resistance either increases, decreases, or stays constant with flow [19]. This is probably because mean orifice area changes [20] either as a result of an increase in maximum geometric orifice area or because the valve opens more quickly or both. Despite these concerns, a high transaortic resistance at rest remains an easily calculated corroborating sign of severe stenosis. DOBUTAMINE STRESS Dobutamine can be used both to grade aortic stenosis and to test for left ventricular contractile reserve. Doses between 5 and 20 g/kg/min are given in increments of 5 g/kg/min approximately every 5 minutes [12,20]. There must be careful medical supervision because of the risk of arrhythmia. In general, severe aortic stenosis is associated with a relatively large rise in mean pressure difference and a relatively small rise in orifice area. By contrast, moderate stenosis is associated with a small rise in mean pressure difference and a larger rise in effective orifice area. However, there is no rigid division into fixed and relative aortic stenosis as was suggested by a small preliminary study [21]. We showed that in patients with normal left ventricular function, the effective orifice area increased by about 25% in all grades of aortic stenosis, although the absolute increase was less in severe stenosis than in moderate or mild stenosis [20]. Severe stenosis is suggested [13] by a failure of the effective orifice area to increase above 1.2 cm 2, or more formally [20] by a compliance of less than 0.2 cm 2 /100 ml.s -1. Compliance is calculated from the plot of effective orifice area and flow. Alternatively, the effect of flow on pressure difference can be used. The pressure drop or flow slope is calculated from the plot of mean pressure difference against flow during dobutamine infusion. Severe stenosis is associated with a slope steeper than 0.1 mm Hg/ ml.s -1 [18], although a simpler practical guide is a rise in the mean pressure difference above 30 mm Hg at any time during dobutamine infusion [13]. In fact, surgical results in patients with low flow aortic stenosis depend less on the grade of stenosis than on the ability of the left ventricle to recover [12,13]. Therefore, the most important observation during dobutamine infusion is whether the ventricle improves. If the systolic velocity integral reliably increases by more than 20%, the surgical mortality is relatively lower and the midterm outlook relatively better than if there is no such increase (Fig. 1). Monin et al. [12 ] noted a surgical mortality of 8% in patients with flow reserve and 50% in those without flow reserve. Survival at 5 years was 88% after surgery in the presence of flow reserve, but between 10% and 25% if there was no reserve [12 ]. Nishimura et al. [13] noted a mortality of 7% in patients with contractile reserve compared with 33% in those without.

4 472 Valvular, Myocardial, Pericardial, and Cardiopulmonary Disease Figure 1. Dobutamine stress in low gradient, low ejection fraction aortic stenosis. This patient presented in heart failure. The left ventricle was dilated and globally hypokinetic as illustrated in this parasternal long-axis late systolic frame (A). The left ventricular ejection fraction was 15% and the peak transaortic velocity was 3.0 m/s (B) despite a dobutamine infusion at a dose of 5 µg/kg/min. Increasing the dose to 10 µg/kg/min increased the systolic velocity integral by 33%, from 4.8 to 6.4 cm. The patient recovered well and now has normal exercise tolerance although he is in atrial fibrillation. The M-mode before surgery during dobutamine infusion is shown in (C) and after surgery in (D). Treatment Surgery For the patient with a mean transaortic pressure difference above 30 mm Hg, surgery can be undertaken with higher than average risk, but with the likelihood of good long-term survival. In patients with a mean pressure difference below 30 mm Hg at rest, surgery can be undertaken at acceptable risk if the systolic velocity integral rises by greater than 20% during dobutamine echocardiography and if the effective orifice area by the continuity equation remains less than 1.2 cm 2. If there is pulmonary hypertension, the risk is higher and the long-term result less good [22], but surgery remains indicated. If the patient has severe aortic stenosis, but the stroke volume does not increase by more than 20% during dobutamine infusion, the surgical risk is high and long-term outcome poor [12 ]. However, the outlook without surgery is dismal so that in selected patients without significant comorbidity it may be reasonable to proceed with surgery after careful discussion with the patient and family. In patients in whom echocardiography has shown relatively moderate aortic stenosis with or without flow reserve, the literature suggests that surgery should not be performed. However, in individual cases the decision to withhold surgery remains difficult. If the effective orifice area is well above 1.2 cm 2 with dobutamine, and there is an obvious alternative cause for the left ventricular dysfunction such as coronary disease with a fixed scar, it is reasonable not to operate. If, however, the effective orifice area is around 1.2 cm 2, the left ventricular dysfunction is global and there is no obvious alternative cause, surgery should still be considered. Anecdotally, patients with relatively moderate stenosis can develop significant left ventricular impairment during intercurrent illnesses and then both require and do well with aortic valve replacement.

5 Low Gradient, Low Ejection Fraction Aortic Stenosis Chambers 473 Before surgery it is necessary to perform angiography to determine coronary anatomy. However, the aortic valve should not be crossed because this approximately doubles the risk of death, stroke, pulmonary edema, and cardiogenic shock to around 7% [23,24]. A recent study showed an additional risk of subclinical cerebral infarcts on magnetic resonance scanning in 22% of patients in whom the valve was crossed, but in none in whom coronary angiography alone was performed [25 ]. Nonsurgical treatment The definitive treatment remains surgery. In patients who are judged too ill for immediate surgery, a brief period of medical resuscitation with diuretics and dobutamine should be considered. There is some uncertainty about the safety of dobutamine in such patients, but there appears little risk of arrhythmia at doses up to 10 g/kg/min. Nitroprusside was shown to be effective and safe in a recent study [26 ]. The dose was started at a mean of 14 g/min and titrated over 24 hours to produce a mean systemic blood pressure between 60 and 70 mm Hg at a dose of 128 g/min. Balloon valvotomy has been used on occasions as a bridge to surgery, but carries unacceptably high risk and is not widely accepted [3,26,27]. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Lindroos M, Kupari M, Heikkila J, Tilvis R: Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993, 21: Horstkotte D, Loogen F: The natural history of aortic valve stenosis. Eur Heart J 1988, 9(suppl E): ACC/AHA 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 (Committee on Management of Patients with Valvular Heart Disease) [no authors listed]. J Am Coll Cardiol 1998, 32: Carabello BA: Aortic stenosis. N Engl J Med 2002, 346: Chambers J, Das P: Exercise testing in aortic stenosis. Heart 2001, 86: Schwartz E, Baumann P, Manthey J, et al.: The effect of aortic valve replacement on survival. Circulation 1982, 66: Connolly HM, Oh JK, Orszulak TA, et al.: Aortic valve replacement for aortic stenosis with severe left ventricular dysfunction. Prognostic indicators. Circulation 1997, 95: Sasayama S, Ross J, Franklin D, et al.: Adaptations of the left ventricle to chronic pressure overload. Circ Res 1976, 38: Carabello BA, Green LH, Grossman W, et al.: Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure. Circulation 1980, 62: Cannon JR, Zile MR, Crawford FA, et al.: Aortic valve resistance as an adjunct to the Gorlin formula in assessing the severity of aortic stenosis in symptomatic patients. J Am Coll Cardiol 1992, 20: Scwammenthal E, Vered Z, Moshkowitz Y, et al.: Dobutamine echocardiography in patients with aortic stenosis and left ventricular dysfunction: predicting outcome as a function of management strategy. Chest 2001, 119: Monin J, Monchi M, Gest V, et al.: Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients. Risk stratification by low-dose dobutamine echocardiography. J Am Coll Cardiol 2001, 37: This together with reference 13 provides the main clinical evidence for managing patients with low gradient, low ejection fraction aortic stenosis. 13. Nishimura RA, Grantham JA, Connolly HM, et al.: Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: the clinical utility of the dobutamine challenge in the catheterization laboratory. Circulation 2002, 106: Zoghbi WA, Galon A, Quinones MA: Accurate assessment of aortic stenosis severity by Doppler echocardiography independent of aortic jet velocity. Am Heart J 1988, 116: Cook RA, Chambers J: The peak to mean pressure gradient ratio: a new method of grading aortic stenosis. Heart 1998, 80(suppl):S36.

6 474 Valvular, Myocardial, Pericardial, and Cardiopulmonary Disease 16. Lewis RP, Rittigers SE, Forester WF, et al.: A critical review of systolic time interval. Circulation 1977, 56: Bruch C, Schermund A, Dagres N, et al.: Severe aortic valve stenosis with preserved and reduced systolic left ventricular function: diagnostic usefulness of the Tei index. J Am Soc Echocardiogr 2002, 15: Takeda S, Rimington H, Chambers J: The relationship between transaortic pressure difference and flow during dobutamine stress echocardiography in patients with aortic stenosis. Heart 1999, 82: Burwash IG, Thomas DD, Sadahiro M, et al.: Dependence of Gorlin formula and continuity equation valve areas on transvalvular volume flow rate in valvular aortic stenosis. Circulation 1994, 89: Das P, Rimington H, Smeeton N, Chambers J: Determinants of symptoms and exercise capacity in aortic stenosis: a comparison of resting haemodynamics and valve compliance during dobutamine stress. Eur Heart J 2003, 24: De Fillipi CR, Peeler RG, Roehill WH: Relationships between left ventricular ejection time, stroke volume and heart rate in normal individuals and patients with cardiovascular disease. Am Heart J 1995, 75: Malouf JF, Enriquez-Sarano M, Pellikka PA, et al.: Severe pulmonary hypertension in patients with severe aortic valve stenosis: clinical profile and prognostic implications. J Am Coll Cardiol 2002, 40: Folland ED, Oprian C, Giacomini J, et al.: Complications of cardiac catheterization and angiography in patients with valvular heart disease: VA cooperative study on valvular heart disease. Cathet Cardiovasc Diagn 1989, 17: Roger VL, Tajik AJ, Reeder GS, et al.: Effect of Doppler echocardiography on utilization of hemodynamic cardiac catheterization in the preoperative evaluation of aortic stenosis. Mayo Clinic Proc 1996, 71: Omran H, Schmidt H, Hackenbroch M, et al.: Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003, 361: A carefully constructed prospective study showing a high rate of silent and overt cerebral infarcts after retrograde left ventricular catheterization for aortic stenosis. This provides further evidence that catheterization should be confined to coronary angiography in these patients. 26. Khot UN, Novaro GM, Popovic ZB, et al.: Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis. N Engl J Med 2003, 348: A recent study confirming earlier work that careful afterload reduction may be effective in patients in heart failure even in the presence of apparently critical aortic stenosis. This challenges the dogma that arterial dilators are absolutely contraindicated in severe aortic stenosis. 27. Safian RD, Warren SE, Berman AD, et al.: Improvement of symptoms and left ventricular performance after balloon aortic valvuloplasty in patients with aortic stenosis and depressed left ventricular ejection fraction. Circulation 1988, 78: