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J Am Coll Cardiol, 2005; 46:2237-2243, doi:10.1016/j.jacc.2004.11.074
© 2005 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: NORMAL QRS DURATION AND RESYNCHRONIZATION

Mechanical Dyssynchrony Assessed by Tissue Doppler Imaging Is a Powerful Predictor of Mortality in Congestive Heart Failure With Normal QRS Duration

Goo-Yeong Cho, MD*,*, Jae-Kwan Song, MD, FACC{dagger}, Woo-Jung Park, MD*, Sung-Woo Han, MD*, Seung-Hyuk Choi, MD*, Young-Cheoul Doo, MD*, Dong-Jin Oh, MD* and Yung Lee, MD*

* Division of Cardiology, Hangang Sacred Heart Hospital, University of Hallym, Seoul, Korea
{dagger} Division of Cardiology, Asan Medical Center, University of Ulsan, Seoul, Korea

Manuscript received August 9, 2004; revised manuscript received October 25, 2004, accepted November 1, 2004.

* Reprint requests and correspondence: Dr. Goo-Yeong Cho, Hangang Sacred Heart Hospital, University of Hallym, Yeongdeungpo-Dong Yeongdeungpo-Ku 94-200, Seoul 150-030, South Korea (Email: cardioch{at}medimail.co.kr).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to test whether the mechanical dyssynchrony assessed by tissue Doppler imaging (TDI) is a predictor of cardiac events in patients with congestive heart failure (CHF) and QRS duration ≤120 ms.

BACKGROUND: The prevalence and prognostic value of mechanical dyssynchrony in patients with CHF and normal QRS duration have not been well clarified.

METHODS: A total of 106 patients (age 63 ± 11 years) with CHF and ejection fraction (EF) <35% were followed serially; TDI was performed using four basal and four mid-left ventricular segments to assess the time to peak systolic point from R-wave on electrocardiogram (Ts). The standard deviation of Ts (Ts-SD) and the maximal temporal difference of Ts (Ts-diff) of eight segments were used as an indicator of mechanical dyssynchrony. Clinical events included readmission due to worsening of CHF, cardiac transplantation, and death.

RESULTS: After 17 ± 11 months of follow-up, the clinical event rate was 33% including all-cause mortality of 19%. Prolonged Ts-SD (>37 ms) and Ts-diff (>91 ms) were associated with a significant increase in all clinical events. By multivariate analysis, Ts-diff (>91 ms) was an independent risk factor of clinical events and mortality regardless of age, EF, QRS duration, and use of beta-blocking agents. Mean event-free survival was 16.3 months (95% confidence interval [CI] 11.9 to 20.7) in patients with Ts-diff >91 ms and 31.6 months (95% CI 28.0 to 35.1) in those with Ts-diff ≤91 ms, respectively (p < 0.001).

CONCLUSIONS: Myocardial dyssynchrony assessed by TDI is a powerful predictor of clinical events in CHF with normal QRS.

Abbreviations and Acronyms
  ACE = angiotensin-converting enzyme
  CHF = congestive heart failure
  CRT = cardiac resynchronization therapy
  ECG = electrocardiography/electrocardiogram
  EF = ejection fraction
  LV = left ventricle/ventricular
  ROC = receiver-operating characteristic
  TDI = tissue Doppler imaging
  Te = time to early peak diastolic velocity from R-wave on electrocardiogram
  Ts = time to peak systolic point from R-wave on electrocardiogram
  Ts-diff = maximal temporal difference of Ts
  Ts-SD = standard deviation of Ts

A common finding in ischemic or non-ischemic cardiomyopathy is abnormal electrical activation, which may delay the timing of ventricular contraction and generate electromechanical abnormality, mainly affecting left ventricular (LV) synchrony and the ventricular contraction and relaxation sequence (1–4). Electrical ventricular dyssynchrony is manifested in electrocardiography (ECG) as a prolongation of the QRS duration and may cause discoordinate contraction of the ventricle (5). Many studies have shown that such electrical conduction delay is associated with diminished cardiac function (6) and is an important prognostic risk factor for morbidity and mortality in patients with congestive heart failure (CHF) (7,8). However, the QRS duration is an indirect correlate but not direct reflection of mechanical dyssynchrony, which is the real substrate that causes a decline in chamber function (5).

Recent studies showed that LV mechanical dyssynchrony is a predictor of severe cardiac events in patients with CHF independently from the QRS duration (9,10). However, whether mechanical dyssynchrony is an independent prognostic factor in CHF without prolongation of QRS duration has not been previously fully described. The aim of this study was to address if echocardiographic systolic and diastolic dyssynchrony measured by tissue Doppler imaging (TDI) is an independent prognostic factor in CHF with normal QRS duration (≤120 ms) regardless of age, etiology of CHF, baseline ejection fraction (EF), or other parameters.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patient characteristics.   Between June 2000 and March 2003, 106 consecutive patients who met the following criteria were prospectively enrolled: 1) dyspnea on exertion (New York Heart Association function class ≥II) for at least three months; 2) bilateral pulmonary congestion on admission; and 3) LV EF <35% and QRS duration ≤120 ms at the time of discharge. Exclusion criteria included age >80 years, atrial fibrillation, significant structural valvular disease, cardiac or cerebral ischemic event within the previous three months, and coexisting malignant disease. Patients with coronary revascularization during the study period were also excluded. All patients were treated with beta-receptor blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, and diuretics at the time of discharge. The dose of a beta-blocker was gradually increased to maximal tolerable dose, and a special emphasis was paid to long-term compliance. The patients or their families were contacted via outpatient clinic at an interval of one month after discharge.

The ischemic etiology of heart failure was defined as one of following criteria: 1) significant epicardial coronary artery stenosis (≥50%); 2) perfusion defect on radionuclide imaging; or 3) history of coronary revascularization. In case of death, the reasons for death were verified from hospital records or a death certificate from the primary physicians. Clinical events included hospitalization due to worsening of heart failure or serious ventricular arrhythmia, heart transplantation, and all-cause mortality. Standard surface 12-lead ECGs were recorded at a paper speed of 50 mm/s. The QRS duration was measured with a caliper, and the longest QRS duration was obtained.

Echocardiography.   Standard echocardiography with Doppler studies was performed using a commercially available system (Vivid 5, Vingmed-General Electric, Holten, Norway). Left ventricular dimensions were measured using M-mode echocardiography according to the guidelines of the American Society of Echocardiography. Global LV function was assessed from apical views by measuring LV end-diastolic volume, LV end-systolic volume, and LV EF, using the modified biplane Simpson rule. Mitral regurgitation was graded mild (regurgitation jet area ≤4 cm2), moderate, or severe (regurgitation jet area >8 cm2 and regurgitation volume ≥60 ml).

For TDI, color Doppler frame rates varied between 99 and 130 frames/s depending on the sector width of the range of interest and aliasing velocities between 16 and 32 cm/s. At least three consecutive beats were stored digitally. The digital cine loops were analyzed using commercially available software (Echopac 6.3.6, General Electric-Vingmed) by off-line analysis. Myocardial regional velocity curves were constructed from the digitally stored images. For a detailed assessment of the regional myocardial velocity, the sampling volume was placed at the following segments: LV septal, anterior, lateral, and inferior segments at both basal and middle levels utilizing apical four- and two-chamber views. For measurement of time intervals, the R-wave of the QRS complex was used as the reference point, from which the time to peak myocardial sustained systolic velocities (Ts) during ejection phase and early peak diastolic velocities (Te) were measured and expressed in milliseconds. For the assessment of systolic dyssynchrony, the standard deviation of Ts (Ts-SD) and the maximal temporal difference of Ts (Ts-diff) of all eight segments were calculated. For diastolic dyssynchrony, Te-SD and Te-diff were also calculated. Intraobserver agreement was calculated by repeated measurement of the same recording in 10 patients with an interval of one month. The correlation coefficients for Ts-SD, Ts-diff, Te-SD, and Te-diff were 0.95, 0.95, 0.96, and 0.97, respectively.

Statistical analysis.   The data were analyzed using the SPSS software (version 11.5, SPSS Inc., Chicago, Illinois). Summary data are expressed as mean values ± SD or percentage of patients. Comparisons of the baseline characteristics between the groups were performed with independent-sample t test and with the chi-square test for categorical variables. The percentage of patients with clinical events by level of mechanical dyssynchrony was assessed by the Pearson chi-square test. The optimal Ts-SD and Ts-diff cutoff values for predicting of primary end points were determined by the receiver-operating characteristic (ROC) curve. Cumulative survival curves for clinical events or all-cause mortality were constructed according to the Kaplan-Meier analysis, and the differences between the curves were tested by log-rank statistics. Hazard ratios and 95% confidence intervals were calculated for each categorical variable using cutoff values in the Cox regression model. A p value <0.05 was considered statistically significant.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Patient characteristics.   A total of 106 patients, whose mean age was 63 ± 11 years, were included in the study. The mean QRS duration was 98 ± 12 ms. The ischemic heart disease was the etiology of CHF in 65%. During a mean follow-up of 17 ± 11 months, clinical events developed in 33.0% (35 of 106 patients), and mortality was 18.9% (20 of 106 patients); 18 patients died of CHF, one patient died of unexplained shock after hip surgery, and the other patient died due to uncontrolled infection.

The baseline clinical and echocardiographic characteristics are summarized in Table 1. Patients with clinical events showed higher mean age, higher prevalence of ischemic heart disease, longer QRS duration, and lower prescription of beta-blockers. There were no differences in the baseline two-dimensional echocardiographic variables, including Te-SD and Te-diff, between groups. However, Ts-SD and Ts-diff were significantly prolonged in patients with clinical events (p < 0.001). There was a weak positive correlation between mechanical dyssynchrony and the QRS duration (r = 0.26, p = 0.007).


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  		Table 1. Clinical and Echocardiographic Characteristics Between Two Groups
 
Cardiac events according to Ts-SD and Ts-diff.   Frequency of cardiac events according to each level of Ts-SD and Ts-diff is depicted in Figure 1. Cardiac events increased in proportion to Ts-SD and Ts-diff. We constructed the ROC curve to determine the optimal Ts-SD and Ts-diff cutoff value for predicting clinical events; the optimal cutoff value of Ts-SD was 37 ms with 68% sensitivity and 71% specificity, and Ts-diff was 91 ms with sensitivity and specificity of 70% and 68%, respectively (Fig. 2).



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  		Figure 1 Percent of patients with clinical events and death by level of standard deviation of time to peak systolic point from R-wave on electrocardiogram (Ts-SD) (A) and the maximal temporal difference of Ts (Ts-diff). (B) *p < 0.01; {dagger}p = 0.01; {ddagger}p = 0.05.

 


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  		Figure 2 Receiver-operating characteristic curve to determine the optimal cutoff value of the standard deviation of the time to peak systolic point from R-wave on electrocardiogram (Ts-SD). (A) and the maximal temporal difference of Ts (Ts-diff). (B) for predicting clinical events. AUC = area under the curve.

 
Predictors for clinical events and mortality.   Clinical and echocardiographic parameters were investigated for their predictive value for clinical events and mortality by univariate and multivariate analysis (Table 2). In a univariate analysis, Ts-SD >37 ms, Ts-diff >91 ms, age >65 years, longer QRS duration, and no use of beta-blockers were significantly associated with development of clinical events and mortality. Ischemic etiology of heart failure is associated with only clinical events. However, by multivariate analysis, Ts-diff >91 ms was identified as the independent predictor of clinical events and mortality.


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  		Table 2. Hazard Ratio by Cox Regression Analysis for Clinical Events and All Causes of Mortality
 
Kaplan-Meier analysis.   The mean clinical event-free survival and mean survival evaluated by Kaplan-Meier analysis were longer in patients with Ts-SD ≤37 ms or Ts-diff ≤91 ms than in those with Ts-SD >37 ms or Ts-diff >91 ms (Figs. 3 and 4).Go



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  		Figure 3 Clinical event-free survival (top) and mortality-free survival (bottom) by Kaplan-Meier analysis. Patients with time interval from R-wave to peak systolic tissue velocity (Ts)-SD >37 ms were expressed in dashed lines and those with Ts-SD ≤37 ms in solid line. CI = confidence interval.

 


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  		Figure 4 Clinical event-free survival (top) and mortality-free survival (bottom) by Kaplan-Meier analysis. Patients with maximal temporal difference of time to peak systolic point from R-wave on electrocardiogram (Ts-diff) >91 ms were expressed in a dashed line and those with Ts-diff ≤91 ms in a solid line. CI = confidence interval.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The main finding of this study is that detection of LV systolic dyssynchrony using TDI was a powerful independent predictor of clinical events or all causes of mortality in CHF with normal QRS duration regardless of age, EF, QRS duration, etiology of CHF, and use of beta-blockers. However, diastolic dyssynchrony was not associated with prognosis.

Despite intensive medical therapy with beta-blockers, ACE inhibitors, and spironolactone, chronic CHF is a common disease that has a poor prognosis and periods of incapacitating symptoms necessitating recurrent hospital admissions (11). Because the clinical diagnosis of CHF includes a wide spectrum of clinical presentations and functional status, there is considerable variation in their prognosis. Many methods are available to determine early predictors of mortality in CHF patients, including ventricular function, hemodynamic and biomechanical parameters, peak oxygen consumption, and electrophysiologic parameters (12). And some studies have examined the significance of QRS prolongation as a noninvasive predictor of increased mortality in patients with moderate-to-severe heart failure (7,8,13,14). The QRS duration ≥120 ms has been shown to have high specificity for LV dysfunction (6). However, the QRS duration is an indirect index of mechanical dyssynchrony. The relation between the electrical ventricular activation time and the mechanical sequence of the systolic phase remains incompletely identified. Recent studies have revealed that mechanical dyssynchrony with or without electrical dyssynchrony adversely influences ventricular function due to discoordinate contraction (5,10). Bader et al. (10) reported that in optimally treated patients for CHF, the QRS duration appears to be poorly correlated with the presence of electromechanical dyssynchrony based on TDI. They also suggested that mechanical dyssynchrony is predictive of heart failure worsening, independent of the QRS duration and LV EF. Therefore, prolongation of the QRS duration may be helpful in identifying the presence of ventricular dyssynchrony, but it should not be considered a specific marker of mechanical dyssynchrony. In our study, there was a poor, although significant, positive correlation between the QRS duration and Ts-SD (r = 0.26, p < 0.01), and systolic mechanical dyssynchrony is common in CHF patients with normal QRS duration. This observation is consistent with a previous report by Yu et al. (15), which documented intraventricular asynchrony in 51% of patients with narrow QRS complex.

Cardiac resynchronization therapy (CRT) is an emerging treatment option for patients with severe CHF with ventricular dyssynchrony (16–18). For patients with severe heart failure whose QRS duration is >130 ms, CRT improves exercise tolerance and quality of life, and reduces hospitalization or mortality from progressive heart failure (16,17). In our study, in which only patients with normal QRS duration were included, mechanical dyssynchrony defined as a prolonged Ts-SD or Ts-diff is a powerful predictor of clinical events and all causes of mortality; if the Ts-diff is more than 110 ms, more than 50% of patients develops clinical events. Achilli et al. (19) recently demonstrated that CRT provides a significant clinical and functional benefit that was similar in patients with wide or normal QRS duration if they have echocardiographic evidence of asynchrony. Therefore, CRT seems to be an effective treatment option in patients with severe heart failure and objective evidence of mechanical dyssynchrony, regardless of QRS duration. However, although this manuscript deals with patients with QRS duration ≤120 ms, those with events had significantly wider QRS duration (103 vs. 95 ms). This may indicate that although both groups are in the normal range, QRS duration is still an important factor in patients with CHF.

Study limitations.   This study has several important limitations. First, we have not utilized the previously proven predictors such as B-type natriuretic peptide, peak oxygen consumption, and electrophysiologic parameters in their multivariate regression model. Second, patients with both ischemic and non-ischemic CHF were included in this study. Some patients with ischemic CHF had regional wall motion abnormalities, which might influence mechanical dyssynchrony. And, the proportion of patients receiving beta-blockers was different between the two groups. During the follow-up period, more patients in the group with events were discontinued on the beta-blockers because of hypotension, weakness, and edema. Therefore, ischemic etiology and the use of beta-blockers were included for investigation of their predictive values of cardiac events by multivariate analysis. Nevertheless, mechanical dyssynchrony is still an independent predictor of cardiac events regardless of etiology and the use of beta-blockers.

Conclusions.   Our study demonstrates that mechanical dyssynchrony assessed by TDI is an independent prognostic factor in CHF with normal QRS duration. Future studies are necessary to prospectively examine the clinical benefit of CRT in these selected groups of patients with normal QRS duration and mechanical dyssynchrony.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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