Chapter 52 Diastolic Stress Echocardiography

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1 Chapter 52 Diastolic Stress Echocardiography SATISH C. GOVIND AASHA S. GOPAL ANATOLI KIOTSEKOGLOU SAMIR K. SAHA PHYSIOLOGY OF DIASTOLE Left ventricular (LV) diastole can typically be defined as a phase seen in the cardiac cycle after aortic valve closure. During this time interval, LV receives blood from the left atrium (LA) prior to ejection: Diastole has four phases: 1. Isovolumic relaxation (IVR) period 2. Early rapid filling phase 3. Diastasis 4. Late filling phase due to atrial systole In the case of LV, during the IVR phase, LV pressure declines rapidly due to the closure of the aortic valve, and when this pressure falls below the left atrial pressure (LAP), the mitral valve opens, thereby ending the phase of IVR. With the opening of the mitral valve, there is early rapid filling from the LA to LV. In a normal healthy person, during the early part of this filling, about 70% 80% of the blood is emptied from the LA passively. As a late feature, remaining 20% 30% empties by active contraction of LA during atrial systole. The interval between these two emptying phases is called diastasis (equalization of pressure between the chambers), during which there is scant movement of blood between LA and LV and where the mitral valve remains in a semi-open position. Immediately after left atrial contraction, the mitral valve closes because of rapid fall of pressure in the LA at the end of diastole, paving the way for the aortic valve to open. This brief phase after mitral valve closing and before opening of the aortic valve is called isovolumic contraction, which heralds the onset of LV systole. By transthoracic standard Doppler echocardiography, two main diastolic phases can be characterized, mitral E (early filling) and A (late filling) wave velocities, obtained by placing the pulsed-wave (PW) Doppler sample volume between the tips of the mitral valve with cursor parallel to the blood flow 1. Doppler signals can be better analysed, when using a sweep speed of 100 m/s or more. A slower sweep speed maybe used in irregular heart rhythms, such as in atrial fibrillation or when there are frequent ectopics. In routine practise, LV diastolic function assessment must include, blood Doppler sampling at the tip of the mitral leaflets, tissue Doppler imaging (TDI) at the mitral annulus, LA volume assessment and tricuspid regurgitation measurement (for estimating pulmonary artery pressure). Using echocardiographic parameters like mitral E-velocity, e at mitral annulus, E/e ratio, LA volume and pulmonary artery systolic pressure (PASP), a diagnosis of diastolic dysfunction is made and LV filling pressure (LVFP) is estimated ( Fig ). Grading of LV diastolic dysfunction is made by taking an integrative approach using multiple parameters of blood Doppler and TDI, which sometimes may require measurement of pulmonary vein Doppler velocities also. LEFT VENTRICULAR FILLING PRESSURES LV diastolic pressures include LVFP, left ventricular end-diastolic pressure (LVEDP) and mean LAP. LVFP is indicative of changes in the early diastole, while LVEDP reflects changes at the end of diastole, and LAP reflects the average pressure 2. In practise, a normal LV diastolic function means normal LAP both during rest as well as during exercise. LV diastolic pressures are reflected by pulmonary artery wedge pressure (PAWP) by right heart catheterization. A normal PAWP is 5 10 mm Hg, while in overt heart failure, PAWP often exceeds 20 mm Hg during resting conditions. 431

2 432 SECTION V Cardiac Imaging A B C D Figure Transthoracic echocardiographic images are shown for left ventricular diastolic function evaluation: (A) blood Doppler sampling at mitral inflow, (B) tissue Doppler sampling at mitral annulus, (C) left atrial volume, biplane estimation and (D) tricuspid regurgitation for pulmonary artery pressure estimation. LVFP is assessed noninvasively by a combination of standard Doppler echocardiography (mitral E-velocity) and TDI. TDI e -wave velocity is obtained by PW Doppler sample volumes placed at the septal and lateral corners of the mitral annulus in the apical four-chamber view. In most instances, an average of septal and lateral e -wave velocities is taken in the measurement of E/e, where it is derived by dividing the mitral blood flow E-velocity, by the averaged TDI annular e -velocity ( Fig ). A normal value is 8, while a ratio of and above is considered abnormal, indicative of elevated filling pressure. A value of 8 12 is considered to be in the grey zone. This method is not applicable in the presence of mitral annular calcification, mitral valve repair or prosthetic mitral valve. DIASTOLIC STRESS ECHOCARDIOGRAPHY DEFINITION In diastolic stress echocardiography, patients are subjected to physical exercise in association with echocardiographic monitoring when being evaluated for possible cardiac cause of exertional dyspnoea. A positive test is indicated by an echocardiographic demonstration of a rise in LVFP (E/e ) during the test, especially when seen with exercise limiting symptoms. In a positive test, the LVFP estimated is normal at rest, but increases under conditions of stress, especially seen in patients with structural abnormalities of the heart (like LV hypertrophy) who invariably have impaired relaxation of the LV myocardium. LV ejection fraction (LVEF) is preserved in such patients, and in some patients even the resting diastolic parameters may appear to be normal. The explanation for this increase in E/e or LVFP is that it could possibly be due to the manifestation of LV diastolic dysfunction as an exercise-induced phenomenon which in turn leads to increased LVFP. Hence, the goal of this stress test is to unmask elevated LVFP during peak exercise, typically using the E/e ratio which is often associated with raised PASP. The American Society of Echocardiography (ASE) expert document on diastolic function states that the most appropriate

3 Chapter 52 Diastolic Stress Echocardiography 433 A B C Figure Transthoracic echocardiographic images for left ventricular filling pressure estimation (E/e ), showing measurement of (A) mitral inflow E-velocity, (B) e velocity at lateral annulus and (C) e velocity at medial annulus. (E/e is increased in the images shown above.) patient population for diastolic exercise testing is the group of patients with grade 1 diastolic dysfunction, having delayed myocardial relaxation with normal mean LAP at rest 3. It has recently proposed a simplified approach to diastolic function assessment. PATHOPHYSIOLOGY In everyday life, humans do varied physical activities like walking, running, bending and squatting. Under normal conditions, these day-to-day activities do not lead to elevation of LV diastolic pressure. When normal individuals engage in any type of physical activity, it is possible to demonstrate by echocardiography an increased blood flow into the LV that is reflected by a rise in mitral Doppler E-wave velocity, small A-velocity wave and short deceleration time. At the same time, myocardial motion can also be measured using TDI, where, relaxation is shown to be increased as seen by an increased e -velocity. Therefore, the LV E/e ratio which is reflective of LVFP is always within a normal range of less than 8, because normal filling pressure is maintained. In these same healthy individuals, during an exercise, mean pulmonary pressures will not rise above the normal value of 25 mm Hg. However, in many patients with subclinical disease like hypertension and diabetes or those with overt cardiac disease like coronary artery disease (CAD) with preserved ejection fraction, diastolic function is impaired. They have impaired relaxation and decreased compliance, and in a number of patients there may even be an associated increase in LV diastolic pressure with pulmonary hypertension, and this can clinically manifest as breathlessness on exertion. RATIONALE FOR USING E/e Published work in the past has established that LV diastolic pressure can be estimated by various echocardiographic methods. A number of studies have shown the superiority of E/e to reliably estimate increased LVFP when compared to other methods. Resting E/e was found to have the best correlation, though modest, and the most robust in assessing LVFP and predicting exercise capacity especially in patients with LV hypertrophy and impaired relaxation. Applying this parameter, E/e has been found to be quite reliable during physical exercise, especially in supine bicycle ergometry, and also validated in the presence of tachycardia, thus capable of estimating LVFP and assessing exercise capacity quite effectively. Correlation of LVFP at exercise corresponds quite well with its resting values. It has also been found to have a better correlation when assessed at lower levels of filling pressures,

4 434 SECTION V Cardiac Imaging while at higher levels of LVFP it still can maintain acceptable sensitivity and specificity. It has been found that postexercise E/e is increased more in patients with limiting dyspnoea than any other limiting symptom, and, if E/e is high during exercise, it is associated with worse functional status. INDICATIONS AND CONTRAINDICATIONS Diastolic stress echocardiography is indicated in subjects with unexplained exertional dyspnoea, especially in those who have underlying myocardial or structural heart disease. Another important indication for stress test is to differentiate between normal ageing and latent LV diastolic dysfunction with or without failure, as many older but healthy adults may have grade 1 diastolic dysfunction with dyspnoea of noncardiac cause. Patients with LVEF less than 50%, those with significant CAD, sustained arrhythmias, patient s with more than moderate valvular disease and those with pulmonary disease are usually excluded from this test. Patients before undergoing diastolic stress echo should ideally have gone through tests which can assess CAD, valve disease and significant pulmonary disease. PROCEDURE Diastolic stress echocardiography should be performed using tests reflective of physiological conditions such as supine bicycle or exercise treadmill tests, whereas the use of a nonphysiological test like dobutamine stress echocardiography is not indicated. Potential limitation of diastolic stress testing test is the challenge of measuring a fused E and e at high heart rates and also to counter the effects of exercise in the form of hyperventilation and swinging of heart with increased respiration, which come in the way of good image acquisition. Echocardiography Before start of the exercise, all echocardiography data are acquired for comparison with images obtained at peak exercise, with primary focus on the LV diastolic parameters. A routine evaluation of valves, LV size, thickness, LVEF and wall motion abnormalities is made, along with LA volume measurement. Important Doppler parameters acquired are mitral inflow velocities (E- and A-wave) and TDI of mitral annulus e in the apical four-chamber view. E/e is calculated for LVFP, and tricuspid regurgitation peak velocity is measured for estimating pulmonary artery systolic pressure. Passive Leg Raising Passive leg raise has been used at bedside to unmask elevated filling pressure 4 ( Fig ). Passive leg raise transiently elevates preload. The test can be performed on a reclining bicycle with both the legs elevated perpendicular to the torso and with the knees bent to about degrees. Alternatively, Figure Diastolic volume stress test in a subject with cardiac amyloidosis. Top panels: early mitral inflow E-velocity at rest (left) and during leg raise (right). Bottom panels: pulmonary vein atrial reversal velocity at rest (left) and during leg raise (right). These findings are indicative of elevated filling pressure, postpassive leg raise.

5 Chapter 52 Diastolic Stress Echocardiography 435 the legs can be passively lifted and rested on a chair with the torso slightly moved to the left side for better image acquisition. Some laboratories use a 3-min leg raise as a volume-dependent stress to the heart. Advantage of a leg raise test is that the heart rate remains within a favourable range thereby keeping the mitral inflow velocities (E and A) separated. Exercise It is a symptom limited test, where either it is a treadmill exercise or the patient lays supine doing a bicycle exercise. During peak exercise, heart rate usually increases proportional to the level of exercise. Resting and peak echocardiographic images for diastolic function are obtained, and whenever possible, with breath-hold at end expiration ( Fig ). In case of supine bicycle test, patient exercises for 3 6 min approximately and the number of watts of exercise is documented. This test has the advantage where continuous imaging can be done during the test and good quality images can be acquired. Another advantage is that in a supine position there is an increase in end-diastolic ventricular volumes, increased wall tension and oxygen demand, and this can better demonstrate diastolic functional reserve. The capacity of the ventricle to accommodate filling in diastole which is necessary to increase the cardiac output without raising LVFP is defined as diastolic functional reserve. Diastolic stress testing using a supine bicycle to unmask elevated filling pressure, particularly in the elderly is feasible 5. In exercise testing, patients are encouraged to perform maximal exercise, while images are acquired in left lateral decubitus position, both at rest and at peak exercise. One to two minutes of rest immediately on the examination bed after exercise, almost always lowers the heart rate to a level where the fused E- and A-wave velocities are split and better delineated, which allows for better estimation of LVFP using the E/e ratio. The test can be discontinued if there is limiting dyspnoea, chest pain, generalized fatigue, sustained arrhythmias or marked ST changes on the electrocardiogram. The test is considered positive when during peak exercise: average E/e 14 or septal E/e ratio 15, with peak TR velocity 2.8 m/s. Postexercise, an E/e 13 is highly specific (90%) for elevated LV diastolic pressure with moderate sensitivity (63%). Speckle-Tracking Echocardiography Two-dimensional (2D) speckle-tracking echocardiography (STE) with its inherent advantages as a non-doppler and angle-independent modality has been used to study myocardial deformation 6. E/e ratio is obtained, exclusively using TDI, since 2D Figure Diastolic stress echocardiography images (Bruce protocol, treadmill) in a female subject with dyspnoea on exertion. Her averaged E/e ratio at rest was 10 (upper panel) that increased to 24 (lower panel) during peak exercise, suggesting exercise-induced increase in left ventricular filling pressures.

6 436 SECTION V Cardiac Imaging STE obtained E/e ratio has not been validated. As a non-doppler and angle-independent method, with potential advantages, it is important that 2D STE obtained LV filling pressure be investigated and validated in the near future. 2D STE can reliably quantify atrial motion during all the three dynamic phases during ventricular systole (reservoir strain) and diastole (conduit and booster strain). The wide dispersion of LV strain in heart failure with preserved ejection fraction (HFPEF) may limit the applicability of E/e ratio in these patients. Rotational deformation that involves both longitudinal subendocardial fibres as well as obliquely arranged subepicardial fibres and untwisting rate may in theory at least become a more robust marker of diastolic dysfunction in this population, given the heterogeneity of aetiologies behind HFPEF. One can speculate that right and left atrial strain imaging using 2D STE may add both diagnostic and prognostic values in HFPEF. NT-proBNP As some investigators question the exclusive use of E/e ratio in the diagnosis of HFPEF, some have looked to estimate NT-proBNP, which can be considered as a surrogate of ventricular stretch, during peak exercise. However, there is not enough evidence. In a pilot study to assess the role of exercise training in HFPEF, NT-proBNP level did not correlate with other variables including peak exercise oxygen consumption. Also, the peptide level remained same during the test period and did not differ between subjects that underwent physical training versus those who did not, in contrast to E/e ratio and other diastolic markers that improved after exercise training. The authors suggested that in HPEF, a conglomerate of variables is needed to establish diagnosis and to follow prognosis 7. DIASTOLIC STRESS TEST AND HEART FAILURE WITH PRESERVED EJECTION FRACTION The European Society of Cardiology recently released a guideline for the diagnosis and treatment of heart failure where resting values of LV diastolic parameters are used in the diagnosis of HFPEF 8. These resting parameters have been challenged by some investigators who consider them to be less sensitive in the diagnosis of HFPEF. They have been critical of resting E/e ratio alone being used as a surrogate of LVFP for diagnosing HFPEF. In a systematic review and a meta-analysis, they found a very low predictive capability of resting E/e ratio. They concluded that there is insufficient evidence to support that E/e alone can reliably estimate LVFP in preserved LVEF. The diagnostic accuracy of E/e to identify or exclude elevated LVFP in HFPEF is thus limited and requires further validation in future well-designed prospective clinical trials 9. They stated that they found a poor to mediocre correlation between E/e and LVFP, and suggested use of multiple indices for diagnosis of HFPEF. In the meta-analysis however, no stress studies were included. Interestingly, using a combination of echocardiography and invasive catheterization, investigators have shown that PAWP correlated well with E/e ratio both at rest as well as during exercise 10. Not only that, addition of exercise echocardiographic data (E/e ratio 14) improved sensitivity (90%) and thus negative predictive value also, but decreased specificity (71%). A decreased specificity means that it would not be possible to rule out cardiac dyspnoea in about 30% of subjects. A similar result was found in another study, where dyspnoea and reduced exercise capacity were studied to investigate the association between exercise E/e ratio and exercise capacity ( 8 metabolic equivalents, METs). Not only a postexercise E/e ratio was highly specific (90%), the exercise E/e value could also classify subjects below and above 8 METS of exercise 11. E/e also correlated well with LV diastolic pressure both at rest and during exercise. This work can be considered as a validation of diastolic stress echocardiography in suspected patients with unexplained dyspnoea in the background of diabetes mellitus or hypertensive heart disease, where resting echocardiographic data alone should not be used in the diagnosis of HFPEF. The reason for this could be that if one looks at the myocardial architectural alterations in HFPEF, it has been stated that there is wide dispersion of LV deformation that is necessary to maintain a normal LVEF. Because of such regional dispersion, resting E/e ratio may not always reveal an abnormal filling pressure. There is increasing evidence that diastolic stress test is a more reliable tool for diagnosis of HFPEF, particularly because more than one measure needs to be used to detect HFPEF. LIMITATIONS One of the most important limitations of diastolic stress test is the lack of consensus and paucity of clinical studies. The new simplified ASE guideline for LV diastolic function assessment is a step forward to initiate more clinical and multicentre

7 Chapter 52 Diastolic Stress Echocardiography 437 studies along with exercise testing on this particular patient population. Whether application of diastolic stress test is possible on a larger and wider population with coronary, valvular and myocardial pathologies remains to be seen. Currently though the application of diastolic stress test remains invaluable to identify dyspnoea of cardiac disease as seen in HFPEF. Whether all or only a selective population of subjects like those with grade 1 LV diastolic dysfunction should undergo diastolic stress test also have to be seen. As of now, the application has far less clinical appeal compared with more conventional stress echocardiography methods to diagnose CAD. Diagnosis of diastolic dysfunction in arrhythmia, moderate to severe mitral valve disease and hypertrophic cardiomyopathy and other special populations still remains a huge challenge. FUTURE DIRECTIONS There are strong potential benefits, both diagnostic and prognostic in the inclusion of E/e and PASP as parameters in all exercise stress echocardiographic studies. It is probably as important as parameters used to assess LV systolic function. It is also relevant to look at the clinical outcome of these patients in order to make diastolic stress echocardiography more clinically acceptable and for it to gain acceptance into routine clinical practice. Just like estimation of three-dimensional (3D) LVEF has gained prominence, use of STE in either 2D or 3D format could throw some new light, where newer, easier and more accurate surrogates for estimating LVFP could be helpful. It is moderately helpful in predicting prognosis and can be considered for adding to standard methods of exercise testing. CONCLUSIONS Diastolic function continues to occupy a prominent position in clinical cardiology. Diastole is more energy dependent than systole and when dysfunction sets in, symptoms gradually follow this. With increasing incidence of heart failure and after the recognition of HFPEF, there is growing interest in this clinical entity since a significant percentage of the general population has been shown to be having LV diastolic dysfunction. With an ever-increasing rise in population of patients with diabetes, hypertension and CAD, and also an ageing population, identifying LV diastolic dysfunction and HFPEF using LVFP at rest and exercise becomes important. Diastolic stress echocardiography can be a key test in the diagnosis of these symptomatic patients to detect HFPEF in suspected cases of cardiac dyspnoea. A failure to increase pulmonary artery pressures with exercise indicates poor prognosis and efforts should be made to assess this in all tests. The finding that an E/e cut-off value of 13 or more identifies patients with LV diastolic pressure of more than 15 mm Hg, independent of the presence of myocardial ischaemia 11, makes it a strong case for continued clinical and research application of diastolic stress echocardiography, preferably using supine bike or treadmill exercise. REFERENCES 1. Nagueh, S. F., Appleton, C. P., Gillebert, T. C., Marino, P.N., Oh, J. K., Smiseth, O.A., et al. ( 2009 ). Recommendations for the evaluation of left ventricular diastolic function by echocardiography. European Journal of Echocardiography. 10 ( 2 ), Otto, C. M. (2013). Text book of clinical echocardiography (5th ed.). Philadelphia, Pennsylvania, USA: Saunders. 3. Nagueh, S., Smiseth, O., Appleton, C., Byrd, B., Dokainish, H., Edvardsen, T., et al. ( 2016 ). 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8 438 SECTION V Cardiac Imaging European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure, 18 ( 8 ), Sharifov, O., Schiros, C., Aban, I., Denney, T., & Gupta, H. ( 2016 ). Diagnostic Accuracy of Tissue Doppler Index E/e (for evaluating left ventricular filling pressure and diastolic dysfunction/heart failure with preserved ejection fraction: A systematic review and meta-analysis. Journal of the American Heart Association, 5, pii: e Obokata M, Kane G, Reddy Y, Olson T, Melenovsky V, & Borlaug B. ( 2016 ). Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction Clinical Perspective. Circulation, 135, Burgess, M. I., Jenkins, C., Sharman, J. E., & Marwick, T. H. ( 2006 ). Diastolic stress echocardiography: Hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise. Journal of American College of Cardiology, 47 ( 9 ),