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European Journal of Echocardiography Advance Access published online on May 1, 2008
European Journal of Echocardiography, doi:10.1093/ejechocard/jen146
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Prolonged total isovolumic time predicts cardiac events following coronary artery bypass surgery

Gani Bajraktari1, Alison Duncan2, John Pepper2 and Michael Henein3,*

1 Second Division of Cardiology, University Clinical Centre of Kosova, Prishtina, Kosovo
2 Royal Brompton Hospital, London, UK
3 Umea Heart Centre, Umea University, Sweden

Received 19 December 2007; accepted after revision 21 March 2008.

* Corresponding author. Tel: +46 90 7851428; fax: +46 90 137633. E-mail address: henein{at}googlemail.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aims: Left ventricular (LV) systolic dysfunction may be associated with compromised stroke volume, which may be caused by asynchrony, reflected on the prolongation of isovolumic time (t-IVT). To assess the prognostic role of Doppler echocardiographic measurements in predicting cardiac events after coronary artery bypass grafting (CABG).

Methods and results: The study included 74 patients undergoing routine CABG. A pre-CABG Doppler echocardiographic assessment of LV dimensions, filling and ejection was performed and t-IVT was determined as [60 – (total ejection time + total filling time)]. Follow-up period was 18 ± 12 months. Of the 74 patients (age 65 ± 16 years, 59 males), 29 underwent hospital admission for a cardiac event or died. There were no differences in age, gender, incidence of previous infarct or mitral regurgitation, LV-EDD (left ventricular end-diastolic dimension), left atrial or right ventricular size in patients with cardiac events compared with those without events. Left ventricular end-systolic dimension (LV-ESD) was greater (4.5 ± 0.9 vs. 3.9 ± 0.9 cm, P = 0.003), fractional shortening (FS) was lower (21 ± 4 vs. 32 ± 8%), E:A ratio and Tei index were higher (2.1 ± 0.8 vs. 1.0 ± 0.6 and 0.9 ± 0.3 vs. 0.6 ± 0.3, all P < 0.001), and t-IVT was longer (16 ± 5 vs.10 ± 4 s/min, P < 0.001) in patients with events. Multivariate predictors of post-CABG events (odds ratio 95% confidence interval) were low FS [0.66 (0.50–0.87), P < 0.001], high E:A ratio [l4.13 (1.17–14.60), P = 0.028], large LV-ESD [0.19 (0.05–0.84), P = 0.029], and long t-IVT [1.37 (1.02–1.84), P = 0.035].

Conclusion: Despite satisfactory surgical revascularization, long t-IVT and systolic dysfunction suggest persistent ventricular dyssynchrony that contributes to post-CABG cardiac events. Early assessment of such patients for potential benefit from electrical resynchronization may optimize their cardiac performance and hence clinical outcome.

Keywords: Coronary artery disease; Coronary artery bypass grafting; Doppler echocardiography; Total isovolumic time


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Left ventricular (LV) function is considered the most important predictor of survival in patients with coronary artery disease (CAD).1 In those with impaired LV function after myocardial infarction or following coronary artery bypass graft (CABG) surgery, global ejection fraction (EF), end-systolic volume, and restrictive LV filling have all been reported to predict peri-operative mortality.2–4 Restrictive LV filling, which reflects raised left atrial pressure, has long been known to carry a poor prognosis,5 particularly when it persists at fast heart rate during dobutamine stress and fails to revert to non-restrictive filling pattern.6–10 Patients with CAD also often have activation disturbances.11,12 With broadening of the QRS duration, total isovolumic time (t-IVT), or the total period in the cardiac cycle when the heart is neither filling nor ejecting, prolongs.13 This is a recently proposed parameter that is easily measured and highly reproducible. Although t-IVT normally shortens with dobutamine stress,13 this response is attenuated in patients with CAD, irrespective of the cavity size. The aim of our study was to assess the prognostic role of t-IVT in predicting cardiac events in patients undergoing CABG surgery, and to compare its predictive ability with conventional Doppler echocardiographic systolic (global LV function) and diastolic (restrictive LV filling) measurements.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients
This study included 74 unselected patients, mean age 65 ± 16 years (59 males) who underwent routine CABG surgery, between 2000 and 2003 by a single cardiac surgeon at the Royal Brompton Hospital. Inclusion criteria were: (i) significant CAD (>70% stenosis at coronary angiography); (ii) full pre-operative Doppler echocardiographic examination and (iii) available post-operative clinical data for the follow-up period, from hospital and general practitioners. No patient had atrial fibrillation, serious ventricular arrhythmias, valvular heart disease, more than moderate functional mitral regurgitation, or inadequate echocardiographic examination. Patients were divided into two groups according to the occurrence of post-operative cardiac events during the follow-up period (18 ± 12 months). Cardiac events were defined as death or post-operative hospitalization for angina, breathlessness, or arrhythmia and were obtained from clinical notes and general practitioner questionnaires.

Echocardiography
Echocardiographic examination was performed using a Phillips Sonos 5500 echocardiograph with a multi-frequency transducer, and harmonic imaging as appropriate. Cross-sectional, two-dimensionally guided M-mode recordings of LV minor axis were performed using the left parasternal long axis view with the cursor at the tips of the mitral valve leaflets. LV minor axis dimensions were measured at end diastole (the onset of the QRS complex) and at end systole (the first high frequency vibration of the aortic component of the second heart sound on the superimposed phonocardiogram, A2) using leading edge methodology. A2 was identified as the sound synchronous with the onset of the closure artefact on the aortic Doppler recording. Fractional shortening (FS) was calculated as the percentage fall in LV cavity dimension during systole with respect to that at end-diastole. EF was estimated using Simpson’s biplane method. Left atrial dimension was measured from M-mode recordings with the cursor crossing the aortic root at the level of the aortic valve leaflets. LV long axis M-mode recordings were obtained with the cursor positioned at the lateral and septal angles of the mitral ring and right ventricular (RV) long axis recording with the cursor positioned at the lateral angle of the tricuspid ring. All M-mode recordings were zoomed to obtain best images for accurate measurements.

Transaortic Doppler velocity was obtained from the apical five-chamber view with the pulsed wave sample volume placed just beneath the aortic valve leaflets. LV ejection time was measured as the interval between the onset of forward aortic flow and the onset of the aortic valve closure artefact. LV filling velocities were obtained from the apical four-chamber view with the sample volume placed by the tips of the mitral valve leaflets. Peak early (E-wave) and late (A-wave) diastolic LV filling velocities, and E-wave deceleration time (EDT) were measured. LV filling pattern was considered ‘restrictive’ when E:A ratio was >2 and EDT <140 ms. Total filling time was measured from the onset of the E-wave to the end of the A-wave. All recordings were acquired with an ECG (lead II) and a phonocardiogram superimposed. Total IVT was calculated as 60 (total ejection time + total filling time) and was expressed in s/min. Tei index was calculated as the ratio between t-IVT and ejection time.14,15

Mitral regurgitation severity was assessed by colour and continuous wave Doppler and was graded as mild, moderate, or severe according to the jet distance from the valve orifice and flow velocity profile, respectively, in line with the recommendations of the American Society of Echocardiography.16 Likewise, tricuspid regurgitation was assessed by colour flow and continuous wave Doppler from the apical four-chamber view. Retrograde transtricuspid pressure drop >35 mmHg was taken as a sign of pulmonary hypertension when the right atrium was not dilated.

Reproducibility
Two investigators analysed echocardiographic measurements, both unaware of the original diagnosis and of the other’s findings. Intraobserver and interobserver variability were each assessed in 20 patients. Duplicate measurements of filling and ejection times were made. Intraobserver coefficient of variability ranged from 3.5 to 5.2% and interobserver variability from 4.2 to 6.4%.

Data analysis
Data is presented as mean ± standard deviation. Continuous data were compared between groups using a two-tailed unpaired Student t-test. Discrete variables were compared using {chi}2 test or Fisher’s exact probability test as appropriate. Multiple logistic regression analysis was used to identify the independent echocardiographic correlates with cardiac events. Clinical variables, e.g. age, sex, and prior myocardial infarction were adjusted. All analyses were performed using Statview 4.5 (Abacus Concepts, Berkley, CA, USA). P-value <0.05 indicated statistical significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 74 patients studied, 29 had a cardiac event (death or hospitalization) after CABG. Previous myocardial infarction was present in 17/29 patients with a cardiac event compared with 21/45 patients with no cardiac event ({chi}2 = 1.00, P = ns). In total, 57 patients had functional mitral regurgitation (mild in 49 and moderate in 9); mitral regurgitation of any grade was present in 24/29 patients with cardiac event and 33/47 with no cardiac event ({chi}2 = 0.88, P = ns). Thirteen patients had echocardiographic evidence for pulmonary hypertension based on tricuspid regurgitation retrograde pressure drop.

Patients with cardiac events vs. no events
Left ventricular end-systolic dimension (LV-ESD) was significantly greater (4.5 ± 0.9 vs. 3.9 ± 0.9 cm, P = 0.003), FS was reduced (21 ± 4 vs. 32 ± 8%, P < 0.001), and septal long axis amplitude was lower (0.9 ± 0.3 vs. 1.1 ± 0.4 cm, P = 0.04) in patients who had cardiac events compared with those without events (Table 1), though there was no significant difference in EF. E-wave velocity and E:A ratio were both higher (1.0 ± 0.3 vs. 0.7 ± 0.2 cm/s, and 2.1 ± 0.8 vs. 1.0 ± 0.6, respectively P < 0.001), A-wave velocity was lower (0.5 ± 0.2 vs. 0.8 ± 0.2 cm/s, P < 0.001), and EDT was shorter (147 ± 45 ms vs. 189 ± 63 ms, P = 0.002) in patients with events compared with those without events but there was no difference in LA size or pulmonary artery pressure between the two groups. Total IVT was longer (16 ± 5 vs. 10 ± 4 s/min) and Tei index was higher (0.9 ± 0.3 vs. 0.6 ± 0.3, both P < 0.001) in the events group. No RV measurement was significantly different between the two groups.


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  		Table 1 Doppler echocardiographic data

 
Predictors of cardiac events
In the univariate analysis model, a number of measurements predicted cardiac events in the studied group: FS, t-IVT, Tei index, E and A-wave velocities, EDT, LV-ESD, and LV septal long axis amplitude (Table 2). However, the only independent variables that predicted post-operative cardiac events were low FS (odds ratio 0.66, P < 0.001), high E:A ratio (l4.13, P = 0.028), increased LV-ESD (odds ratio: 0.19, P = 0.029), and long t-IVT (odds ratio 1.37, P = 0.035). Of the patients who had a post-operative cardiac event, 31% had a t-IVT > 15 s/min (upper 95% normal confidence interval) compared with only 6% in those without events ({chi}2 = 9.98, P < 0.01).


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  		Table 2 Predictors of post-coronary artery bypass grafting cardiac events

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Findings
Our results show that measurements of overall ventricular systolic and diastolic dysfunction are the most accurate predictors of post-surgical myocardial revascularization events. In addition, markers of global ventricular asynchrony, prolonged t-IVT are particularly independent predictors of post-operative events in this group.

Ventricular asynchrony
Mild asynchrony is a normal finding; however exaggerated asynchrony is compatible with either advanced conduction disease or myocardial disease, for which CAD is the commonest etiology.17 Ischaemic asynchrony varies in its severity, particularly with prior myocardial infarction. Revascularization results in regression of ventricular asynchrony, and in some, complete normalization of segmental function particularly in the absence of myocardial scarring or fibrosis. Organized asynchrony may represent an irreversible remodelling process that may have its effects on global LV function. M-mode, tissue Doppler velocities, strain and strain rate, speckle tracking, and myocardial perfusion echocardiographic techniques have demonstrated variable sensitivities in assessing segmental function.18–20 Each of these techniques has its advantages and disadvantages, particularly with regards to differences in frame rate. On the other hand, measurements of global ventricular function including EF, FS and Tei index have also demonstrated varying sensitivities in assessing such patients.21

Total isovolumic time
Recently, t-IVT has been invoked as a sensitive marker of global ventricular asynchrony.22 It represents the time wasted in the cardiac cycle when the ventricle is neither filling nor ejecting. For the sake of avoiding measurement errors of the two isovolumic time intervals, t-IVT is easily measured as the sum of the total filling and ejection times subtracted from the cycle length, R–R interval. The shorter the t-IVT the more efficient the ventricular cavity function.14 Late onset of myocardial shortening delays the onset of ejection and shortens its duration. Likewise, the late onset of segmental lengthening delays the onset of ventricular filling and shortens its duration, hence the prolonged t-IVT. Thus, in the absence of raised atrial pressure t-IVT may indirectly reflect the overall burden of ventricular asynchrony on ventricular functional efficiency.

Successful myocardial revascularization tends to normalize segmental asynchrony, irrespective of the procedure used, surgical or interventional.22,23 This results in shortening of the two isovolumic times and the period of raised wall tension in systole and early diastole. The end result is prolonged total ejection and filling times and increased stroke volume. We have previously shown that t-IVT correlates closely with changes in cardiac output as well as prediction of exercise capacity in heart failure patients with stress.24,25 We have also shown that the longer the t-IVT the better the LV response to cardiac resynchronization therapy.26,27 In this study we have identified a number of echocardiographic measurements that predicted clinical events after surgical coronary revascularization. An enlarged cavity is consistent with a remodelled ventricle, while increased end-systolic diameter reflects impaired systolic function, particularly at the basal segment and restrictive filling ‘high E:A’ is consistent with raised left atrial pressure. However, the independent predictive value of total IVT suggests the important additional role of ventricular asynchrony in determining patients clinical outcome. Even in the absence of significant epicardial CAD, ventricular asynchrony itself may cause subclinical subendocardial ischaemia, particularly at fast heart rate, which may predispose to clinical instability.

Clinical implications
t-IVT is an easy and highly reproducible measurement that reflects the degree of ventricular asynchrony. Patients with values of 15 s/min and above are commonly seen in those who develop post-operative cardiac events and who may benefit from cardiac resynchronization therapy.27 A thorough assessment of these patients soon after surgery and during follow-up may suggest a need for electrical correction of ventricular asynchrony as an attempt to improve clinical outcome.

Limitations
This is a retrospective study but relied on conventional means of patient management as it is conducted in a tertiary referral centre. Tissue Doppler recordings were not complete for all patients therefore we were unable to compare our findings with those previously published. We elected not to include detailed segmental analysis that might rather add confusion to the easy conventional and practical measurements that could be obtained in most echocardiography departments. Since the study was retrospective review of already managed patients according to conventional clinical protocol we were unable to include in our analysis early post-operative data in all patients.

Conclusion
Despite complete revascularization by CABG, persistent systolic dysfunction and additional long t-IVT that reflect persistent post-operative ventricular dyssynchrony, contribute to follow-up cardiac events. Early identification of such patients with persistent asynchrony may highlight potential benefit from electrical resynchronization and hence optimized cardiac performance and clinical outcome.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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