Tissue Doppler Image-Derived Measurements During Isovolumic Contraction Predict Exercise Capacity in Patients With Reduced Left Ventricular Ejection Fraction
Eun Joo Cho, MD, PhD,
Giuseppe Caracciolo, MD,
Bijoy K. Khandheria, MD,
D. Eric Steidley, MD,
Robert Scott, MD,
Walter P. Abhayaratna, MD,
Krishnaswamy Chandrasekaran, MD,
Partho P. Sengupta, MD, DM*
Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona
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Abstract
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Objectives: We explored the incremental value of quantification of tissue Doppler (TD) velocity during the brief isovolumic contraction (IVC) phase of the cardiac cycle for the prediction of exercise performance in patients referred for cardiopulmonary exercise testing (CPET).
Background: Experimental studies have shown that rapid left ventricular (LV) shape change during IVC is essential for optimal onset of LV ejection. However, the incremental value of measuring IVC velocities in clinical settings remains unclear.
Methods: A total of 82 subjects (age 53 ± 14 years, 56 men) were studied with echocardiography and CPET. Reduced LV ejection fraction (EF) (EF <50%) was present in 38 (46%) subjects. Pulsed-wave annular TD velocities were averaged from the LV lateral and septal annulus during isovolumic contraction (IVCa), ejection, isovolumic relaxation, and early and late diastole (Aa) and compared with peak oxygen consumption (VO2) and percentage of the predicted peak VO2 (% predicted peak VO2) obtained from CPET.
Results: Patients with reduced EF had lower IVCa (6.3 vs. 4.5 cm/s, p = 0.04), ejection (7.7 vs. 5.5 cm/s, p < 0.001), and Aa velocities (7.9 vs. 6.6 cm/s, p = 0.04). Similarly, % predicted peak VO2 was lower in patients with reduced EF (52.9% vs. 73.1%, p < 0.001) and correlated with the variations in IVCa (r = 0.7, p = 0.001). Multivariate analysis of 2-dimensional and Doppler variables in the presence of reduced LV EF revealed only IVCa and Aa as independent predictors of % predicted peak VO2 (r2 = 0.612, p = 0.02 for IVCa and p = 0.009 for Aa). The overall performance of IVCa in the prediction of exercise capacity was good (area under the curve = 0.86, p < 0.001).
Conclusions: Assessment of TD-derived IVC and atrial stretch velocities provide independent prediction of exercise capacity in patients with reduced LV EF. Assessment of LV pre-ejectional stretch and shortening mechanics at rest may be useful for determining the myocardial functional reserve of patients with reduced EF.
Key Words: left ventricular dysfunction • tissue velocity • exercise capacity
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Abbreviations and Acronyms
| | Aa = annular tissue velocity during late diastolic period | | CPET = cardiopulmonary exercise test | | Ea = annular tissue velocity during early diastolic period | | EF = ejection fraction | | IVC = isovolumic contraction phase | | IVCa = annular tissue velocity during isovolumic contraction period | | LV = left ventricle/ventricular | | LVEF = left ventricular ejection fraction | | MET = metabolic equivalent | | ROC = receiver-operator characteristic | | TD = tissue Doppler | | VCO2
= carbon dioxide production | | VE = minute ventilation | | VO2
= oxygen consumption | | % predicted peak VO2
= predicted peak oxygen consumption |
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The isovolumic contraction (IVC) phase of the cardiac cycle initiates interactions between cardiac myofilaments through energy-dependent calcium fluxes in the myoplasm and sarcolemma (1,2). Approximately 50% of total myocardial oxygen consumption (VO2) is expended for a rapid rise in left ventricular (LV) pressure during IVC (3). In vitro experiments using skinned muscle preparations have suggested that this energy-dependent early shortening sequence may stretch activate the cardiac muscle tissue for modulating the force and duration of contraction (4–6). Shortening mechanics during IVC thus may be important for functionally adapting to physiological states with high energy consumption and VO2 such as exercise.
Transient reshaping of LV geometry during IVC is registered on tissue Doppler (TD) imaging as biphasic longitudinal myocardial velocity spikes (7). The positive component of TD-derived IVC velocity spikes has been shown to correlate with the rate of change in LV pressure (8). Furthermore, IVC velocity spikes are associated with the energy efficient sequence of LV intracavity blood flow redirection through vortex ring formation (9–12). In the present study, we evaluated the incremental value of TD-derived peak positive IVC velocity as a noninvasive parameter for the prediction of exercise efficiency in patients referred for cardiopulmonary exercise testing (CPET). We hypothesized that TD-derived IVC velocity would be independently related to peak VO2 and predicted peak oxygen consumption (% predicted peak VO2).
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Methods
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Between January 2007 and August 2008, 193 patients with complaints of dyspnea underwent CPET for objective assessment of exercise capacity and a detailed transthoracic echocardiographic examination at Mayo Clinic Arizona. Patients with moderate or severe valve lesions (n = 30, 15.5%), paced rhythm or ventricular assist device (n = 38, 19.7%), atrial fibrillation (n = 10, 5.1%) and significant lung disease (n = 5, 2.6%), liver or renal failure (n = 61, 31.6%), and congenital heart disease (n = 25, 13.0%) were excluded from the study. Based on left ventricular ejection fraction (LVEF), patients were classified into 2 groups: reduced LVEF (EF <50%; n = 38, 46%) and normal LVEF (EF  50%; n = 50, 54%).
Echocardiography.
Echocardiography and CPET were performed within 1 week (2.5 ± 2.3 days). All patients were examined at rest in the left lateral decubitus position. The echocardiographic techniques and calculations of different cardiac dimension and volumes were performed according to the recommendations of the American Society of Echocardiography (13). LVEF by 2-dimensional echocardiography was obtained by modified biplane Simpson's method from apical 4- and 2-chamber views. LV dimensions and wall thickness were made in parasternal long axis with M-mode cursor positioned just beyond the mitral leaflet tips, perpendicular to the long axis of the ventricle. LV diameter in diastole and systole, LV mass, and fractional shortening were measured. Left atrial volume was calculated from areas measured in apical 2- and 4-chamber views and indexed by body surface area. Left atrial total emptying fraction was calculated by dividing differences between largest and smallest left atrial volume with largest left atrial volume.
Mitral flow velocities.
The mitral flow velocities were recorded with pulsed-wave Doppler with the sample volume placed at the tip of the mitral valve tips from the apical 4-chamber view. From the mitral valve inflow velocity curve, peak E-wave velocity and its deceleration time, and peak A-wave velocity were measured.
TD imaging.
Myocardial velocities were recorded using a standard pulse-wave Doppler technique as previously described (14). High-frequency signals in IVC velocities were filtered using a Nyquist limit adjusted to a velocity range of –15 to 20 cm/s. Gains were minimized to allow for a clear tissue signal with minimum background noise as shown in Figure 1. Peak contraction and relaxation velocities were averaged from the lateral and septal corners of mitral valve annulus during IVC (IVCa), systolic ejection (Sa), and early (Ea) and late (Aa) diastolic phases of the cardiac cycle at a speed of 100 mm/s (Fig. 1). We also measured isovolumic acceleration at the lateral and medial mitral annulus as the slope of the pre-systolic velocity curve expressed in m/s2 (15).
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Figure 1 Measurement of Annular Tissue Velocities
Peak contraction and relaxation velocities were averaged from the lateral and septal corners of mitral valve annulus during isovolumic contraction (IVCa), systolic ejection (Sa), isovolumic relaxation (IVRa), early (Ea), and late (Aa) diastolic phases of the cardiac cycle at a speed of 100 mm/s.
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CPET.
All patients underwent a maximal exercise stress test on an electrically braked stationary cycle ergometer using ramp protocol (n = 9, 11%) or treadmill test using modified ramp protocol (n = 73, 89%). Previous studies have shown the prognostic thresholds of peak VO2 and minute ventilation/carbon dioxide production (VE/VCO2) slope in patients with heart failure to be similar irrespective of mode of exercise (16). Patients were encouraged to exercise to exhaustion. During the test, patients wore a tightly fitting facemask which was connected to a capnograph and a sample tube enabling online ventilation and metabolic gas exchange measurement. Ventilatory expired gas analysis (as well as spirometry) was performed using a metabolic cart (Medgraphics CPX ULTIMA Cardio 2, Minneapolis, Minnesota). Exercise was started at a work load of 30 W, with further increment of 10 W every minute. All patients were encouraged to exercise to exhaustion, with a peak respiratory exchange greater than 1.1. Peak VO2 was defined as the highest O2 consumption during any stage of maximal exercise that could be sustained for 1 min (or 30 s). Data are expressed as relative values and as percentages of the predicted VO2 as well. Metabolic equivalents was defined per convention as equivalent to the consumption of 3.5 ml of oxygen per kilogram of body mass per minute (17). The VO2, VCO2, VE, respiration rate, respiratory exchange ratios (VCO2/VO2), and other standard respiratory parameters were monitored continuously breath by breath and averaged every 15 s. A 4-lead electrocardiogram recorded heart rate continuously.
Statistical analysis.
All continuous data were reported as mean ± SD, and categorical data as percentage. To determine intraobserver variability, 1 observer (G.C.) measured the myocardial velocities in 25 randomly selected patients. Intraobserver variability was calculated as the difference in 2 measurements of the same subject by 1 observer divided by the mean value. To evaluate the interobserver variability, the myocardial velocities were obtained in 68 patients by 2 independent observers (E.C. and G.C.), each without knowledge of the results obtained by the other. Interobserver variability was calculated as the difference in 2 measurements of the same subjects by 2 different observers divided by the mean value. Independent t test was used for comparisons of continuous variables between patients with normal and reduced EF. Pearson's correlation coefficient was used to reveal relations between 2 continuous variables. The receiver-operator characteristic (ROC) curve was plotted to determine the sensitivity and specificity to predict exercise capacity, and Delong Delong Clarke-Pearson method (Analyse-it software, Microsoft Excel, Redmond, Washington) was used to compare diagnostic power of ROC curves (18). Multiple stepwise regression analysis was used to evaluate the relationship between % predicted peak VO2 and clinical and echocardiographic variables. Variables that showed significant correlations (p < 0.1) with % predicted peak VO2 on simple regression analysis were selected. Statistical analysis was performed with commercially available software (SPSS 12.0 software, SPSS Inc., Chicago, Illinois). A p value <0.05 was considered statistically significant.
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Results
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Baseline clinical features of the patients and the underlying etiologies are shown in Table 1.
Echocardiographic data.
Patients with reduced LVEF had thinner interventricular septum (p < 0.001) and posterior walls (p = 0.003). However, there were no significant differences in LV mass index, indexed left atrial volume, and left atrial total emptying fraction (Table 2). There were no significant differences in transmitral early and late inflow velocities, E/Ea, and E/A (Table 2). However, cardiac index was significantly reduced (p = 0.003) in patients with reduced EF.
Pulse-wave TD data.
The absolute intraobserver differences for measuring TD velocities during IVC were 0.06 ± 1.2 cm/s and the corresponding intraobserver variability were 1.2 ± 2.4%. Annular velocities averaged from the septal and lateral corners of mitral annulus were significantly reduced in patients with reduced EF during IVC (6.3 vs. 4.5 cm/s, p = 0.04), ejection (7.7 vs. 5.5 cm/s, p < 0.001), and late diastolic (7.9 vs. 6.6 cm/s, p = 0.04) phases of the cardiac cycle (Table 3). Similarly, isovolumic acceleration measured during the pre-ejection period and averaged from the septal and the lateral corners of mitral annulus was significantly reduced in patients with reduced EF (1.37 ± 0.53 m/s2 vs. 1.85 ± 0.61 m/s2, p = 0.001).
CPET.
Maximum exercise duration (Table 4) was significantly lower in patients with reduced LVEF (363 ± 123 s vs. 443 ± 102 s, p = 0.006). Similarly, exercise variables like MET at peak VO2 (p < 0.001), peak VO2 at maximal exercise (p = 0.001), and % predicted peak VO2 (p < 0.001) were significantly lower, while VE/VCO2 (p = 0.04) and VE/VO2 (p = 0.03) were significantly increased in patients with reduced LVEF.
Correlation between echocardiographic parameters and CPET.
Correlations between TD velocity, isovolumic acceleration and peak VO2, and % predicted peak VO2 for the entire group and for patients with reduced and preserved EF are shown in Table 5. For patients with reduced EF, of all the echocardiographic and clinical parameters assessed, annular velocities during the IVC period and late diastolic period showed the best correlations (Fig. 2) and were independent predictors for % predicted peak VO2 (Table 6, Online Table 1). The overall performance of IVCa, isovolumic acceleration, and Aa (Fig. 3) in the prediction of exercise capacity was good (area under the curve 0.86, p = 0.001 for IVCa; 0.74, p = 0.02 for isovolumic acceleration; and 0.82, p = 0.003 for Aa).
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Figure 2 Annular Velocities and % Predicted Peak VO2 >50%
Correlation between annular tissue Doppler velocity and % predicted peak oxygen consumption (VO2) in patients with left ventricular systolic dysfunction. Abbreviations as in Figure 1.
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Figure 3 Diagnostic Value of Tissue Doppler-Derived Measurements
The receiver-operator characteristic curve analysis of IVCa, Aa, and isovolumic acceleration (IVA) for prediction of % predicted peak volume of oxygen >50% in patients with left ventricular systolic dysfunction. Area under the curve was 0.86, p value was 0.001 for IVCa; area under the curve was 0.82, p value was 0.003 for Aa; and area under the curve was 0.74, p value was 0.026 for IVA. A cutoff value of 3.8 cm/s for IVCa had 88% sensitivity and 72% specificity, while a cutoff value of 5.8 cm/s for Aa had 81% sensitivity and 65% specificity, and 0.96 m/s for IVA had 95% sensitivity and 50% specificity for predicting % predicted volume of oxygen >50%. Abbreviations as in Figure 1.
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Discussion
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The main findings of this study are: 1) TD-derived IVCa and Aa velocities are significantly attenuated in patients with reduced LVEF; and 2) IVCa and Aa are the only 2 independent echocardiographic predictors for exercise capacity in patients with reduced LVEF. To the best of our knowledge, this is the first study that has evaluated the relationship between isovolumic contraction velocities and exercise performance in patients undergoing CPET.
Echocardiographic predictors of exercise capacity in heart failure patients.
Conventional measures of LV function such as resting EF and Doppler indexes such as peak A velocity or E/A are load-dependent and poorly associated with symptoms and exercise capacity (19–24). Previous studies have correlated TD-derived parameters like early diastolic lengthening velocities (Ea) and E/Ea ratio with the extent of exercise limitation in patients with reduced LVEF (25–28). Recent investigations have further suggested the combined use of systolic ejection and early diastolic TD parameter, rather than isolated measurements, would be essential for proper characterization of the extent of exercise intolerance (29). The duration of the total isovolumic period is a major determinant of peak VO2 (30,31). Moreover, TD-derived isovolumic indexes were previously suggested to be relatively load-independent and therefore more sensitive markers of myocardial contractility than parameters measured during ejection and diastolic filling phases (32,33). The specific contribution of IVC period and the relationship between IVC velocity and peak VO2, however, were previously unknown. Our investigation suggests that IVC contraction and LV stretch velocities resulting from atrial contraction, rather than ejection or early diastolic phase lengthening velocities, provide superior prediction of the exercise performance. In contrast to IVC velocity, IVC acceleration showed weaker correlation with % predicted peak VO2 (r = 0.34, p = 0.044) (Online Fig. 1). The diagnostic power of IVC velocity and acceleration for predicting % predicted peak VO2 >50% were, however, similar (0.80 vs. 0.76, p = NS for the entire group and 0.86 vs. 0.74, p = 0.06 for LVEF <50%).
During electromechanical coupling, influx of Ca2+ activates both energy-producing and energy-consuming processes, providing mechanisms for cardiac muscle to dramatically increase contraction without any change in energetic intermediates (34). Early activated regions of the LV contract, stretching the late activated regions (9). This sequence of early shortening and stretch during IVC provides an intrinsic servo-mechanism for dynamically modulating the force of cardiac muscle contraction and the timing of cross-over into diastole (4–6). LV stretch due to atrial contraction precedes isovolumic contraction, and both may dynamically modulate the forces operating in the ejection and early diastolic phases of the cardiac cycle. For example, in our study we found that IVC velocity correlated with ejection phase velocities (Online Fig. 2). This relationship between the phases of the cardiac cycle may be a potential reason why the diagnostic yield of TD imaging for predicting exercise capacity is improved when Aa and IVCa velocities are incorporated. Witte et al. (35) stressed the role of annular tissue velocity in the late diastolic period and its correlation with peak VO2. Late diastolic stretch velocities reflect left atrial function and the adaptive capacity of the left atrium to compensate for increased diastolic volume and filling pressure of the LV in heart failure patients (36–38). Moreover, the peak of Aa and the positive IVCa velocity spike transit on a continuum as seen on the TD-derived spectral velocity waveforms. The correlation of IVCa and Aa with % predicted peak VO2 may thus reflect atrioventricular events that operate on a continuum and prime the LV for optimal systolic ejection and diastolic suction.
Prognostic value of CPET in heart failure patients.
The term "VO2 max" refers to a plateau in peak oxygen uptake in line with increasing workload during exercise. However, congestive heart failure patients are normally unable to exercise to such a level; therefore, the term peak VO2 is used. Peak VO2 is affected by sex and age. In addition, because oxygen uptake is relativized for body mass, heavier patients with a similar fitness level will have a lower peak VO2. Therefore, when considering an individual patient, one must consider adjustments for age, sex, and body mass of the patient. Assessment of peak VO2 threshold can also be problematic in some heart failure patients due to deconditioning, lack of motivation, and difficulty exercising with a face-mask/mouthpiece in situ. In 1996, Stelken et al. (39) suggested the use of the % predicted peak VO2 for identifying patients at risk for future cardiac event. In their study, % predicted peak VO2 cut point  50% was sensitive in detecting more events than the use of absolute peak VO2 value. Subsequently, Osada et al. (40) reported that for peak VO2 14 ml/kg, peak exercise systolic blood pressure and % predicted peak VO2 (50%) in heart transplant recipients were the 2 most important predictors for the combined end point of death or listing as status 1 transplantation priority. Interestingly, for our study the comparison of TD and exercise parameters revealed superior correlation coefficients between TD parameters and % predicted peak VO2 than with peak VO2. Furthermore, ROC analysis showed TD parameters were able to predict % predicted peak VO2 >50%, whereas similar observations were not seen for peak VO2. The role of % predicted peak VO2 thus needs more careful assessment in future investigations.
Study limitations.
The present study only evaluated the myocardial velocity using TD imaging in the longitudinal direction. Further studies would be required for understanding the value of measuring 2- and 3-dimensional strain deformation using Doppler and angle-independent techniques such as speckle tracking. Future studies would also need to compare the clinical value of measuring LV torsional mechanics in predicting exercise capacity, particularly for the group of patients with preserved EF in whom the longitudinal velocities were unable to predict exercise capacity in our study.
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Conclusions
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Pulsed-wave mitral annular isovolumic velocities measured by TD imaging are useful clinical variables for predicting cardiopulmonary exercise capacity in patients with reduced LV systolic function. Peak stretch and shortening velocities during late diastolic and IVCs of cardiac cycle are significantly attenuated in patients with reduced LVEF and are the only 2 independent echocardiographic predictors of the extent of exercise limitation.
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Appendix
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For a supplementary table and figures, please see the online version of this article.
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Footnotes
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Dr. Khandheria is currently affiliated with Aurora Cardiovascular Services, Aurora Sinai/St. Luke's Medical Centers, Milwaukee, Wisconsin.
* Reprint requests and correspondence: Dr. Partho P. Sengupta, Mayo Clinic Arizona, 777 East Mayo Boulevard, Phoenix, Arizona 85054 (Email: sengupta.partho{at}mayo.edu).
Manuscript received May 7, 2009;
revised manuscript received August 10, 2009,
accepted August 11, 2009.
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Abstract
Methods