Parameters Derived from Myocardial Tissue Doppler Imaging ...

Original

Acta Cardiol Sin 2007;23:254-62

Parameters Derived from Myocardial Tissue Doppler Imaging Associated with Major Events in Patients with Uremia Shih-Hung Hsiao, Shih-Kai Lin, Wei-Chen Huang, Chiu-Yen Lee, Shu-Hsin Yang, Kuan-Rau Chiou and Chun-Peng Liu

Background: High cardiovascular mortality in uremic patients is still a problem. This study was designed to assess some echocardiographic parameters to predict prognosis. Methods: We enrolled 95 patients (19 with coronary arterial disease). All underwent conventional echocardiography and tissue Doppler imaging within 30 minutes before and after hemodialysis (H/D). We measured the ratio of the early-diastolic velocity of mitral inflow (E) to the early-diastolic velocity of the mitral annulus (Em). Patients received 4-year follow-up for major events (any-cause mortality and nonfatal cardiovascular events requiring hospitalization). Results: Thirteen deaths and 11 nonfatal major events occurred. The prevalence of underlying coronary arterial disease was higher in patients with major events than in others (33% vs. 7%), as was the degree of left ventricular (LV) systolic dysfunction (LV ejection fraction 46% ± 10 vs. 52% ± 8). Baseline E/Em, either pre-dialytic or post-dialytic, was significantly lower in event-free patients (pre-dialytic 9.9 ± 3.0 vs. 12.2 ± 4.0, p = 0.01; post-dialytic 9.2 ± 2.9 vs. 12.3 ± 3.6, p = 0.002). On Cox regression, factors significantly affecting outcomes were age, LV ejection fraction, LV mass index (hazard ratio [HR] = 1.021, 95% confidence interval [CI] 1.001-1.039, p = 0.021), and post-dialytic E/Em ³12 (HR = 3.054, 95% CI 1.118-11.184, p = 0.009). Conclusion: Like LV dysfunction and LV mass index, a high post-dialytic E/Em was prognostic of major events.

Key Words:

Echocardiography · Tissue Doppler imaging · Uremia · Cardiovascular mortality

INTRODUCTION

locity divided by early-diastolic mitral annular velocity (E/Em) is correlated with LV relaxation and LV filling pressure, and this ratio has prognostic value in many cardiovascular diseases.9,16-18 An E/Em of > 12 is associated with a high event rate in patients with heart failure. 19 Uremic patients under regular hemodialysis (H/D) for chronic renal failure are associated with a high mortality rate, and cardiovascular events are the major cause of death. 20 Accelerated coronary atherosclerosis seems to be closely related to this excessive mortality. 21,22 Other factors implicated in ventricular dysfunction and mortality are increased LV mass and diastolic dysfunction.23,24 This study was undertaken to evaluate the prognostic value of an E/Em in patients with uremia.

Findings on tissue Doppler imaging (TDI) of the mitral annulus accurately and reproducibly represent global LV systolic or diastolic function.1-15 Many TDIderived parameters are useful for assessing cardiovascular risk. The ratio of early-diastolic mitral inflow ve-

Received: September 18, 2007 Accepted: November 12, 2007 Cardiovascular Center, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. Address correspondence and reprint requests to: Dr. Chun-Peng Liu, MD, Cardiovascular Center, Department of Internal Medicine, Kaohsiung Veterans General Hospital, No. 386, Da-Chung 1st Rd., Kaohsiung 813, Taiwan. Tel: 886-7-342-2121 ext. 2011; Fax: 886-7-3455045; E-mail: [email protected]


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METHODS

Pulsed-wave myocardial TDI TDI was performed with spectral pulsed Doppler signal filters by adjusting the Nyquist limit to 15-20 cm/s and by using the minimal optimal gain. The apical view was chosen to quantitatively assess regional wall motion and to minimize the incidence angle between the Doppler beam and the area of longitudinal wall motion. On the apical 4-chamber view, a 3-mm, pulsed-Doppler sample volume was placed at the level of the basal mitral annulus. Tissue Doppler velocities of longitudinal mitral annular motion were recorded in all six segments of the basal mitral annulus. Pulsed-wave TDI tracings were recorded over five cardiac cycles at a sweep speed of 100 mm/s and used for offline calculations. Peak systolic myocardial velocity (Sm), Em, and peak late-diastolic myocardial velocity (Am) over the mitral annulus were measured. Mean TDI parameters over the six segments were calculated, and the mean Em was used to estimate E/Em. The first echocardiographic study was performed about 10-20 minutes before H/D. Paired measurements were repeated immediately after H/D. Particular care was taken to position the sample volume in the same location whenever possible.

Patient population Beginning in June 2002, we prospectively enrolled 95 patients with uremia (49 women, 50 men) who were receiving regular H/D. We obtained written informed consent from the patients and approval by our hospital’s committee on clinical investigation. All patients received maintenance H/D for ³ 6 months. Patients were excluded if they had any rhythm other than a sinus rhythm or if their images were of inadequate quality for analysis. All patients received conventional echocardiography and myocardial TDI within 30 minutes before or after H/D. A nephrologist performed dry-weight adjustments and regular follow-up for routine blood and biochemical studies. The prevalence of coronary artery disease (CAD) at the initiation of this study was based on past history of positive stress test, perfusion scan, documented myocardial infarction and previous revascularization. Conventional echocardiographic study Using a commercially available ultrasound system (Sonos 5500, Philips, Andover, MA) and a 2.5- or 2.0MHz phased-array transducer, we examined patients in the left lateral decubitus position using standard parasternal long-axis, short-axis, and apical views. One author obtained all measurements according to recommendations of the American Society of Echocardiography. Doppler measurements were made at end-expiration to ensure that patients were not straining. Echocardiographic maximum left atrial volume was measured by biplane area-length from apical 4- and 2-chamber views and indexed to body surface area,25,26 according to the American Society of Echocardiography method for calculation of left atrial volume. LV mass was estimated from measurements of septal and posterior-wall thickness and from dimensions of the LV cavity at end-diastole by using the following anatomically validated equation: LV mass = 0.8[1.04(IVS + LVIDd + LVPW) 3 – LVIDd3] + 0.6, where IVS is the diastolic septal thickness, LVIDd is the diastolic dimension of the LV cavity, and LVPW is the diastolic thickness of the posterior wall. The LV mass index was calculated as LV mass divided by the estimated body surface area. LV and right ventricular ejection fractions were estimated by using the Simpson and modified Simpson methods, respectively.27

Follow up After echocardiography, patients were followed up at our nephrologic clinic for 4 years (mean ± SD 44 ± 7 months). Records and causes of their admissions were ascertained from detailed chart review and from final comments of the nephrologists and cardiologists. We recorded major events, which were defined as anycause mortality and nonfatal cardiac or vascular events with hospitalization. Stroke was considered a vascular event, and positive results on treadmill testing or perfusion scanning with scheduled coronary angioplasty or bypass surgery were included as cardiac events. Unstable angina was defined as angina pectoris with resting, new-onset, and/or crescendo angina. Myocardial infarction was identified as clinical symptoms, new ST-segment change of > 1 mm in two contiguous leads, and increased serum cardiac enzyme levels ³ 2 times the upper limit of normal in our laboratory. Some cases of decompensated septic shock or ulcerative bleeding with concomitant ST-segment changes and elevated cardiac enzyme levels were classified as occult CAD. 255


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RESULTS

Statistical analysis All data were expressed as the mean ± SD. A Paired t-test was used to compare the differences before and after H/D. For multivariate comparison, the study cohort was grouped by whether or not they had major events. Receiver-operating characteristic (ROC) curve analysis was performed to select optimal cut-off values of E/Em to predict major events. Using regular Cox proportional hazards regression, we compared the major-event risks of patients receiving H/D according to the cutoff values of E/Em, with adjustments for potential confounders. Covariates for adjustment were age at study entry, previous CAD, size of the LV chamber, LV ejection fraction, and LV mass index. Patient event-free survival was recorded when mortality or nonfatal cardiac or vascular events occurred or at the end of follow-up, whichever came first. Kaplan-Meier curves of cumulative event-free survival were plotted according to E/Em values. Differences were significant if p < 0.05 with a 95% confidence interval (CI). To determine interobserver variability, mean values from one observer were compared with those of a second observer blinded to the initial results. Mean differences between their measurements were calculated, and the percentage variability was derived as the absolute difference between sets of measurements divided by the mean of the two observations. Intraobserver variability was also calculated with this method.

During follow-up, we recorded 24 major events, including 13 deaths and 11 nonfatal cardiovascular events (Table 1). Eight deaths (cardiac ischemic with decompensated septic shock or with a bleeding peptic ulcer, and sudden death) were associated with myocardial ischemia. CAD was the leading cause of nonfatal events. Baseline characteristics, except for LV mass index and CAD, were similar between patients with and those without major events (Table 2). LV mass indexes and Table 1. Major events and causes No. of cases Death Cardiac ischemia with decompensated septic shock Septic shock Cardiac ischemia with bleeding peptic ulcer and shock Sudden death of unknown cause Malignancy Intracranial hemorrhage

2 1 1

Nonfatal cardiac or vascular event Stroke Stable angina treated with revascularization Heart failure with hospitalization Non-ST-elevation myocardial infarction Unstable angina ST-elevation myocardial infarction

3 2 2 2 1 1

4 3 2

Table 2. Baseline characteristics

Age (yrs) Body weight (kg) H/D amount (kg) Diabetes Hypertension LV mass index (g/m2) Albumin (g/dL) Calcium (mg/dL) Phosphorus (mg/dL) Total cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Hemoglobin (g/dL) CAD Deaths

Patients without major events (n = 71)

Patients with major events (n = 24)

p value

058 ± 14 57 ± 8 02.3 ± 0.9 22 (31) 33 (46) 125 ± 37 03.9 ± 0.4 09.9 ± 0.9 05.7 ± 1.5 180 ± 33 105 ± 23 10.1 ± 1.4 5 (7) 0 (0)

60 ± 16 61 ± 11 2.1 ± 0.9 08 (33) 11 (46) 152 ± 440 3.8 ± 0.4 9.6 ± 0.7 4.9 ± 1.3 184 ± 410 113 ± 240 10.3 ± 1.10 14 (58) 13 (54)

0.490 0.416 0.260 0.230 0.810 0.018 0.090 0.221 0.020 0.628 0.141 0.436 < 0.001 < < 0.001
2 kg of fluid was removed.30 For detailed comparison, the present study was designed to measure echocardiographic parameters just before and after H/D. For patients with CAD and abnormalities in regional wall motion, regional TDI parameters are unlikely to represent global LV diastolic function. Therefore, the mean Em was used to estimate E/ Em. A post-H/D E/Em ³ 12 significantly affected outcomes and was the strongest predictor among all covariates (HR = 3.054). On the contrary, a pre-H/D E/Em ³ 12 did not provide adequate power to predict prognosis in the Cox model. LV filling pressure and pulmonary capillary wedge pressure decrease as preload reduced.31,32 This means that E/Em, like LV filling pressure, is lower after preload reduction with H/D and hints that high post-H/D E/Em values are more important than pre-H/D data. Our method is different to the report of Ie et al,33 but the result is similar. Ie and coauthors concluded that conventional echocardiographic and tissue Doppler parameters were limited in ability to assess the diastolic function just before dialysis due to relative fluid-overloading status. They found those parameters measured twenty-four hours after dialysis did not differ from those taken one hour after dialysis. Therefore, echocardiographic parameters including tissue Doppler imaging are not so good to assess left ventricular diastolic function just before dialysis, so pre-H/D E/Em doesn’t provide adequate prognostic significance, as in our study. Among event-free patients, E decreased more than Em after dialysis, lowering post-H/D E/Em. Em was relatively constant during dialysis among patients with events, though E was somewhat reduced. The combined effect was that E/Em did not change after dialysis. Of interest, pre-H/D and post-H/D E/Em values were highest in patients with events. Event-free patients had low LV

Figure 3. Unadjusted 4-year major event rates according to postdialytic (H/D) E/Em.

Table 4. Adjusted HRs for major events

Age (per yr) LV ejection fraction < 50% Post-H/D E/Em > 12 LV mass index (per g/m2)

HR

95% CI

p value

1.039 1.223 3.054 1.021

1.003-1.120 1.043-4.755 01.118-11.184 1.001-1.039

0.023 0.035 0.009 0.021

CI = confidence interval; E = early-diastolic velocity of mitral inflow; Em = early-diastolic velocity of the mitral annulus; H/D = hemodialysis; HR = hazard ratio; LV = left ventricular.

cm/s (variability 5.8 ± 4.7%); Em, 0.4 ± 0.4 cm/s (variability 5.8 ± 4.9%); and Am, 0.5 ± 0.4 cm/s (variability 5.3 ± 5.1%).

DISCUSSION E/Em is correlated with pulmonary capillary wedge pressure and LV filling pressure.4,9,16 E/Em has been applied to CAD,28 chronic heart failure,19 and intubations in intensive care units.17 In a relatively healthy population with a low anticipated mortality rate, LV filling pressure, as determined from cardiac catheterization and E/Em, was also an independent predictor of future heart failure.29 Patients with uremia may have relative fluid overload before dialysis but relative fluid deficiency after 259


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6. Peteiro J, Garcia-Lara J, Garrido I, et al. A new simple method to assess global left ventricular systolic function based on the sum of regional myocardial velocities. Am J Cardiol 2005;95:550-2. 7. Cardim N, Oliveira AG, Longo S, et al. Doppler tissue imaging: regional myocardial function in hypertrophic cardiomyopathy and in athlete’s heart. J Am Soc Echocardiogr 2003;16:223-32. 8. Zoncu S, Pelliccia A, Mercuro G. Assessment of regional systolic and diastolic wall motion velocities in highly trained athletes by pulsed wave Doppler tissue imaging. J Am Soc Echocardiogr 2002;15:900-5. 9. Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation 2000; 102:1788-94. 10. Palmes PP, Masuyama T, Yamamoto K, et al. Myocardial longitudinal motion by tissue velocity imaging in the evaluation of patients with myocardial infarction. J Am Soc Echocardiogr 2000; 13:818-26. 11. Mishiro Y, Oki T, Yamada H, et al. Evaluation of left ventricular contraction abnormalities in patients with dilated cardiomyopathy with the use of pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1999;12:913-20. 12. Oki T, Iuchi A, Tabata T, et al. Left ventricular systolic wall motion velocities along the long and short axes measured by pulsed tissue Doppler imaging in patients with atrial fibrillation. J Am Soc Echocardiogr 1999;12:121-8. 13. Fukuda K, Oki T, Tabata T, et al. Regional left ventricular wall motion abnormalities in myocardial infarction and mitral annular descent velocities studied with pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1998;11:841-8. 14. Yamada H, Oki T, Tabata T, et al. Assessment of left ventricular systolic wall motion velocity with pulsed tissue Doppler imaging: comparison with peak dP/dt of the left ventricular pressure curve. J Am Soc Echocardiogr 1998 ;11:442-9. 15. Gulati VK, Katz WE, Follansbee WP, Gorcsan J 3rd. Mitral annular descent velocity by tissue Doppler echocardiography as an index of global left ventricular function. Am J Cardiol 1996;77: 979-84. 16. Dokainish H, Zoghbi WA, Lakkis NM, et al. Optimal noninvasive assessment of left ventricular filling pressure: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004;109: 2432-9. 17. Combes A, Arnoult F, Trouillet JL. Tissue Doppler imaging estimation of pulmonary artery occlusion pressure in ICU patients. Intensive Care Med 2004;30:75-81. 18. Nagueh SF, Mikati I, Kopelen HA, et al. Doppler estimation of left ventricular filling pressure in sinus tachycardia. A new application of tissue Doppler imaging. Circulation 1998;98:1644-50. 19. Bruch C, Rothenburger M, Gotzmann M, et al. Risk stratification in chronic heart failure: independent and incremental prognostic value of echocardiography and brain natriuretic peptide and its N-terminal fragment. J Am Soc Echocardiogr 2006;19:522-8.

filling pressures regardless of dialysis; therefore, their low event rate is predictable.

Study limitations First, invasive hemodynamic data were not included. However, our purpose was to assess the prognoses of patients with uremia by using simple and noninvasive methods. We did find that echocardiographic parameters were significant predictors for major events. Second, patients with cardiac rhythms other than a sinus rhythm were excluded. Atrial fibrillation may represent a relatively severe condition in uremic patients. Therefore, selection bias was possible. Third, we used the mean Em of six basal mitral segments to calculate E/Em because of high prevalence of CAD and because of the abnormalities in regional wall motion in our cohort. The representativeness and accuracy of our method should be tested in further studies. In addition, the prevalence of CAD was possibly underestimated due to lack of non-invasive or invasive CAD screen in this study cohort. Therefore, despite the possible positive correlation between major events and the past history of CAD, we couldn’t estimate the true hazard ratio of CAD in our cohort due to lack of right prevalence. Fourth, our data were cross-sectional and couldn’t establish causal relationships between clinical and echocardiographic variables.

REFERENCES 1. Oki T, Tabata T, Yamada H, et al. Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921-8. 2. Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474-80. 3. Farias CA, Rodriguz L, Garcia MJ, et al. Assessment of diastolic function by tissue Doppler echocardiography: comparison with standard transmitral and pulmonary venous flow. J Am Soc Echocardiogr 1999;12:609-17. 4. Nagueh SF, Middleton KJ, Kopelen HA, et al. MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressure. J Am Coll Cardiol 1997;30:1527-33. 5. Garcia MJ, Rodriguez L, Ares M, et al. Differentiation of constrictive pericarditis from restrictive cardiomyopathy: assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108-14. Acta Cardiol Sin 2007;23:254-62

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20. Degoulet P, Legratin M, Aime F, et al. Mortality risk factors in patients treated by chronic hemodialysis. Nephron 1982;31:103-10. 21. Parfrey PS, Harnett JD, Barre PE. The natural history of myocardial disease in dialysis patients. J Am Soc Nephrol 1991;2:2-12. 22. Brown JH, Hunt LP, Vites NP, et al. Comparative mortality from cardiovascular disease in patients with chronic renal failure. Nephrol Dial Transplant 1994;9:1136-42. 23. Foley RN, Parfrey PS, Harnett JD, et al. The prognostic importance of left ventricular geometry in uremic cardiomyopathy. J Am Soc Nephrol 1995;5:2024-31. 24. Pizzarelli F, Dattolol P, Ferdeghini EM, Morales MA. Parameters derived by ultrasonic myocardial characterization in dialysis patients are associated with mortality. Kidney Int 2005;68:1320-5. 25. Ujino K, Barnes ME, Cha SS, et al. Two-dimensional echocardiographic methods for assessment of left atrial volume. Am J Cardiol 2006;98:1185-8. 26. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 27. Miller D, Farah MG, Liner A, et al. The relation between quantitative right ventricular ejection fraction and indices of tricuspid an-

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Original

Acta Cardiol Sin 2007;23:254−62

以組織都卜勒超音波參數來預測洗腎病人的癒後蕭世宏

林士凱黃偉春李秋燕楊淑馨邱寬饒高雄市高雄榮民總醫院心血管中心

劉俊鵬

背景心血管疾病造成的死亡仍是洗腎病人的大問題，本研究在於使用心臟超音波來預測洗腎病人的癒後。方法九十五位洗腎病人接受心臟超音波及心肌組織超音波，在洗腎前後，測量舒張早期二尖瓣血流速與舒張早期二尖瓣心肌組織移動速度比例 (E/Em)，以此來推測洗腎病人四年內的出事率。結果四年內的共有十三人死亡，十一人發生非死亡性之重大事件，研究發現洗腎病人的重大事件多與心血管疾病相關，將病人依出事與否分為兩組，可以發現出事組有較高比例的冠心症患者及心收縮功能不良，洗腎前及洗腎後的 E/Em 也比較高，使用 Cox regression model，發現年紀、心收縮功能、LV mass index (hazard ratio [HR] = 1.021, 95% confidence interval [CI] 1.001-1.039, p = 0.021)、及洗腎後 E/Em (HR = 3.054, 95% CI 1.118-11.184, p = 0.009) 對於評估癒後有重大影響。結論

洗腎後 E/Em 如同心收縮功能一樣，對於評估洗腎病人的癒後有重大影響。

關鍵詞：洗腎病人、心肌組織超音波、心血管疾病、癒後。

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