In this issue of JASE, Studer Bruengger et al . report diastolic exercise data in young nonathletic and endurance-trained healthy individuals, along with maximal oxygen consumption (V o 2max ). They confirm a previous observation from older healthy individuals in that the E/e′ ratio (an echocardiographic estimate of pulmonary capillary wedge pressure) remains within the normal range with exercise in healthy young subjects. Although there was a slight increase in septal E/e′ (overall, 6.8 ± 1.3 to 7.2 ± 1.2, P = .02) and lateral E/e′ (overall, 5.0 ± 0.8 to 6.2 ± 0.9, P < .0001) with exercise, the investigators did not document any difference in the response to exercise between the athletic and nonathletic young healthy groups. Moreover, there was a weak correlation between the percentage of predicted V o 2max and exertional E ( r = 0.28, P = .03) and lateral e′ ( r = 0.32, P = .01), but the strongest predictor was indexed left ventricular (LV) end-diastolic volume ( r = 0.66, P < .0001). Another interesting observation from the study was that diastolic function at rest was largely unrelated to exercise capacity, but exertional early diastolic velocities exhibited a significant association with V o 2max . These findings imply that enhancement of diastolic function during exercise may contribute to increased performance of the athletic heart.
This report comes at the 10th anniversary of our feasibility study of diastolic exercise echocardiography after the initial description of the normal values of diastolic echocardiographic parameters with exercise in a middle-aged healthy control 1 year prior.
Exercise testing was combined with echocardiography for the first time to detect myocardial ischemia in 1979, but it took more than a decade to become established as one of the most helpful clinical stress test modalities. With increased oxygen demand with exercise, myocardium with normal wall motion at rest, if subtended by significant coronary stenosis, develops wall motion abnormality. Normal wall motion at rest does not exclude coronary artery disease, and even a regional wall motion abnormality does not indicate ongoing ischemia unless a patient develops additional wall motion abnormality with a form of stress. Although a major focus for stress testing has been in the evaluation of chest pain syndromes with the assessment of myocardial ischemia or coronary artery disease, dyspnea (assumed to be an angina equivalent) is a more common referral symptom than chest pain in clinical practice. Dyspnea, especially with exertion, can be related to increased LV filling pressures with increased demand, similar to stress-induced wall motion abnormality in patients with coronary artery disease. A normal individual has considerable reserve that can support increased demand from exercise and stress, but when one has significant coronary artery disease or diastolic dysfunction, the normal reserve is significantly reduced, producing clinical symptoms such as chest pain or shortness of breath. This reduced reserve capacity or clinical diagnosis of coronary disease or diastolic dysfunction can be better demonstrated with a stress test designed specifically to assess the reserve.
Patients with diastolic dysfunction may have a similar hemodynamic profile (in terms of cardiac output and filling pressure) at rest as healthy individuals with normal diastolic function. With exercise, normal subjects are able to increase cardiac output without increasing filling pressure significantly, because of increased myocardial relaxation, which results in more efficient early diastolic suction with much lower minimal LV diastolic pressure. Reduced myocardial relaxation is one of the earliest manifestations of mechanical dysfunction of the heart. Relaxation properties gradually decrease with aging and are consistently reduced in all forms of myocardial disease, including myocardial ischemia, hypertensive heart disease, hypertrophic cardiomyopathy, and diastolic heart failure or heart failure with preserved ejection fraction (HFpEF). It has been also shown that patients with diastolic dysfunction display a deficiency in myocardial relaxation augmentation with exercise compared with normal subjects with normal myocardial relaxation. Hence, patients with diastolic dysfunction may be able to achieve the required cardiac output only at the expense of increasing LV filling pressure, because the sufficient early suction mechanism for normal filling during early diastole is not available. This is supported by data from the present study showing that exertional, but not resting, diastolic parameters had significant correlations with maximal oxygen consumption. Similarly, the extent of diastolic reserve correlated well with exercise capacity. The most direct method to evaluate and document LV filling pressure with exercise is hemodynamic cardiac catheterization with exercise. However, this method has an obvious limitation, and several studies have shown a good correlation between E/e′ ratio and invasively obtained pulmonary capillary or LV end-diastolic pressure with exercise or ambulation as well as in the resting state. More important, resting mitral annular early diastolic velocity (e′) measured by Doppler tissue imaging can indicate whether a patient has reduced myocardial relaxation.
During each cardiac cycle, myocardial relaxation initiates LV filling in early diastole, with subsequent LV ejection occurring in systole. When myocardial relaxation is normal, the majority of LV filling occurs during early diastole and the rest with atrial contraction. When relaxation is reduced, the timing and mechanism of filling depend on the status of relaxation and filling pressure. If relaxation is reduced, but filling pressure is still normal, a majority of diastolic filling takes place with atrial contraction. As filling pressure increases with reduced relaxation, the primary initial mechanism of filling is the increased pressure, and atrial contraction may not contribute much for ventricular filling. Normal LV relaxation moves the mitral annulus actively toward the left atrium, which elongates the LV cavity, resulting in the negative intracavitary gradient responsible for diastolic suction. Echocardiography can visualize the motion of the mitral annulus in real time and measure the velocity of the mitral annulus by tissue Doppler. Many studies have shown that the early diastolic velocity (e′) of the mitral annulus has a good inverse correlation with the invasively obtained relaxation parameter τ. Pulsed-wave Doppler can measure velocities of diastolic blood flow. Because early diastolic mitral flow velocity (E) is sensitive to preload (and therefore increases with high filling pressure) and because e′ velocity (which is reduced in all forms of myocardial diastolic dysfunction) is less sensitive to preload, it is not surprising that the E/e′ ratio has been found to have a good correlation with invasively obtained filling pressure at rest and also with exercise.
In 2003, we hypothesized that LV diastolic filling pressure can be estimated with exercise as well as at resting state by E/e′ ratio. There are many other cardiac mechanical, hemodynamic, and echocardiography parameters that change with exercise, such as myocardial strain, twisting, intracavitary gradient, timing intervals, and pulmonary artery systolic pressure. Among them, pulmonary artery systolic pressure measurement with exercise has been found to be helpful in aiding the assessment of diastolic filling pressure with exercise. Our laboratory has shown that the upper normal pulmonary artery systolic pressure is 30 mm Hg at rest and 40 mm Hg with exercise. Exercise-induced pulmonary hypertension (defined as pulmonary artery systolic pressure ≥ 50 mm Hg) is prognostic for adverse outcomes on long-term follow-up, especially when combined with an increase in estimated LV filling pressure.
Before our hypothesis for diastolic stress or exercise test was applied to a patient population, we first had to prove the concept in healthy controls. In 2002, two research fellows working in the Mayo Clinic’s echocardiography laboratory, Fabijan Lulic of Croatia and Jong-Won Ha of Korea, performed an exercise diastolic echocardiography study in 31 healthy subjects (18 women and 13 men; mean age, 59 ± 14 years) without histories of hypertension, coronary artery disease, regular medications, or any other cardiovascular symptoms. All subjects underwent symptom-limited treadmill exercise, and necessary parameters for diastolic function assessment were recorded (mitral inflow velocity, mitral annular velocity from the septum, and tricuspid regurgitation velocity). After achieving functional aerobic capacity of 115%, the peak heart rate was 153 beats/min in average, and diastolic functional parameters were obtained within 2 min of exercise when the heart rate was 90 beats/min. Table 1 reports the mitral inflow and mitral annular velocity changes that were observed.
| Variable | Resting state ∗ | After exercise ∗ | Resting state † | After exercise † |
|---|---|---|---|---|
| Mitral inflow E (cm/sec) | 73 ± 19 | 90 ± 25 | 81 ± 14 | 132 ± 15 |
| Medial e′ (cm/sec) | 12 ± 4 | 15 ± 5 | 14.3 ± 2.5 | 20.3 ± 2.7 |
| E/e′ ratio | 6.7 ± 2.2 | 6.6 ± 2.5 | 6.7 ± 1.4 | 7.1 ± 1.1 |
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