Intraventricular conduction delay: a prognostic marker in chronic heart failure

International Journal of Cardiology 70 (1999) 171–178

Intraventricular conduction delay: a prognostic marker in chronic heart failure q Waqar Shamim*, Darrel P. Francis, Mohammed Yousufuddin, Susan Varney, Masimo F. Pieopli, Stefan D. Anker, Andrew J.S. Coats Royal Brompton Hospital and National Heart and Lung Institute, Cardiac Medicine Department, Sydney Street, London 5 W3 6 NP, UK Received 15 March 1999; received in revised form 26 April 1999; accepted 29 April 1999

Abstract Chronic heart failure (CHF) is associated with high mortality, and there are several established clinical and laboratory parameters that predict mortality in CHF. The purpose of this study was (a) to identify the best ECG parameter that predicts mortality, (b) to evaluate the prognostic marker of ECG against well-established indicators of prognosis. Relevant data from 241 CHF patients were analysed retrospectively. Cardiopulmonary exercise testing and radionuclide ventriculogram were also performed where possible. The mean follow-up period was 31 months. On univariate analysis by the Cox proportional Hazard method, intraventricular conduction delay (IVCD) [P,0.0001, hazard ratio 1.017 (l.011–1.024)] and QTc [P,0.0001, hazard ratio l.012 (1.006–1.017)] were identified as predictors of mortality. On bivariate analysis, IVCD and MVO2 were better predictors when combined together. A model based on multivariate analysis showed that IVCD, MVO2 and left ventricular ejection fraction (LVEF) were the best predictors of mortality. The addition of plasma sodium, age and NYHA class had no added benefit on the predictive power of the model. Further analysis of IVCD and QTc showed that, for different cut-off values, IVCD is better than QTc, and that there is a graded increase in mortality with increasing value of IVCD. We have found that IVCD is an important ECG predictor of prognosis in patients with CHF.  1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Electrocardiography; Prognosis; Heart failure; Mortality; Survival

1. Introduction The prevalence of chronic heart failure (CHF) has increased in the past few decades due to ageing of the population and improved survival from myocardial infarction. It remains a condition with a high mortality rate. The Framingham study showed a 10% annual mortality rate in patients with newly diagnosed heart q

Presented as an abstract at the XXth congress of European Society of Cardiology, Vienna, Austria, August 22–26 1998, and published in abstract form (Eur Heart J 1998;19[suppl]:926). *Corresponding author. Tel.: 144-171-351-8127; fax: 144-171-3518634. E-mail address: [email protected] (W. Shamim)

failure [1]. Once heart failure was detected, only 25% of men and 38% of women were alive at five years, reflecting a six–seven-times higher mortality rate than that of the general population of same age [2]. After an acute myocardial infarction, heart failure carries an even worse prognosis [3]. The poor prognosis of heart failure was confirmed in a study in Rochester, MN, with only a 66% one-year survival after diagnosis [4]. For patients with CHF, the benefits of symptomatic improvement achieved by medical therapy are often terminated by sudden, unexpected death [5]. Attempts to identify high risk subgroups of CHF patients have met with limited success [6–8].

0167-5273 / 99 / $ – see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 99 )00077-7

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There has been much interest in the clinical and investigative features predictive of outcome in patients with CHF [9]. Of the numerous variables that have been studied [10], peak oxygen consumption or total exercise time, right and left ventricular ejection fractions, pulmonary capillary wedge pressure, the presence of ventricular arrhythmias, levels of catecholamines, atrial peptides and plasma sodium are all accepted as important predictors of prognosis in patients with CHF [11–16]. The cachectic state has also recently been described as a strong independent factor for mortality in patients with CHF [17]. Echocardiographic variables have been extensively studied in patients with dilated cardiomyopathy for the evaluation of their association with symptoms and mortality [18]. Houghton et al. [19] showed the importance of ECG in diagnosing heart failure in general practice. Fewer studies have examined ECG parameters as prognostic indicators in CHF. Most that have, have looked for axis, heart rate, PR interval, P wave, ST segment or T-wave features. There are very few studies on other parameters of the ECG, such as QT, QTc or QRS duration. The available studies have small numbers of patients and, as a result, it is difficult to derive definitive conclusions [20,21]. The combination of increasing PR interval and longer QRS duration appears to be a marker of high risk in patients with dilated cardiomyopathy [22], however, a number of questions remain unanswered. The present study aimed to identify the prognostic significance of simple ECG parameters in a large single-centre population of consecutive patients with chronic heart failure.

2. Methods We investigated 364 patients with CHF, assessed in the heart failure unit of the Royal Brompton Hospital. After excluding patients with coincident non-cardiac diseases, poor quality tracings with arrhythmias, 241 patients were left for analysis. We analysed the electrocardiograms of these 241 patients with CHF secondary to left ventricular (LV) systolic impairment, who were seen in our clinic between July 1993 and March 1996. This subset of patients came from all patients assessed by our clinic over this

period after exclusion of patients with significant arrhythmias, including atrial fibrillation, WPW syndrome, supraventricular tachycardia, atrioventricular block or a pacemaker, any other important non-cardiac disease or inability to undergo complete assessment (cardiopulmonary exercise test or radionuclide ventriculography). Patients on antiarrhythmic drugs were subsequently excluded from the study because of their possible effects on the ECG measurements [23]. All patients had stable CHF and were in sinus rhythm. All patients were investigated by electrocardiogram, and most of them by radionuclide ventriculography and cardiopulmonary exercise testing. The majority of patients also had cardiac catheterisation. Clinical information regarding the duration of symptoms and history of any other concomitant disease and drug therapy was obtained at the initial assessment and the results are presented in Table 1. Standard 12-lead electrocardiograms were recorded on a Hewlett Packard XLi Page Writer electrocardiogram (Mode M1700A). The calibration was 0.1 mV/ mm and the paper speed was 25 mm / s. Electronic callipers were used to analyse the ECGs manually. IVCD and QT were measured from the chest lead V2. Results were taken as the average of three readings. QTc was calculated using Bazzett’s formula. Cardiopulmonary exercise testing was performed on a treadmill using a mass spectrometer, as described previously [24]. Table 1 Variables that were analysed History and examination: Aetiology of heart failure NYHA class Heart rate, Mean blood pressure Height, weight, change in weight (cachexia)e , BMI a Electrocardiographic PR interval, IVCD b , QT, QTc Echo parameters LVESD c , LVEDD d MUGAf scan: Left ventricular ejection fraction Right ventricular ejection fraction Blood chemistry: Serum Na 1 level a

Body mass index, b Intraventricular conduction delay, c left ventricular end systolic dimension, d left ventricular end diastolic dimension, e documented unintentional weight loss of at least 5 kg and a BMI of less than 24 kg / in 2 , f multigated acquisition scan.

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Table 2 Patients’ characteristics

Age (years) Height Weight BMI b Peak V0 2 c LVEF e IVCD f QTc g Plasma Na 1 d

All CHF a patients

Comparison by survival status

(n5241)

Died (n575)

Alive (n51 66)

P-value

60 (11) 173 (9) 79 (14) 27 (4) 17.8 (6.8) 28 (14) 121 (33) 445 (5 2) 138 (3)

63 (9) 172 (9) 75 (13) 25 (4) 14.1 (6.2) 22 (12) 137 (35) 461 (57) 137.6 (3.4)

59 (11) 173 (9) 81 (14) 27 (4) 19.4 (6.4) 31 (13) 114 (28) 436 (41) 138.6 (2.9)

0.0029 0.81 0.0007 0.0004 ,0.0001 ,0.0001 ,0.0001 0.0003 0.03

a

g

Chronic heart failure, b body mass index, c peak oxygen consumption, d sodium, e left ventricular ejection fraction, f intraventricular conduction delay, corrected Qt interval.

All patients were followed from the date of their initial assessment and enrolment in this study until their death or until 30th March 1998. Their death or survival status was confirmed by the National Registry and also by hospital clinic attendance, general physician’s records and was confirmed by telephone call to the patient’s residence. No patient was lost to follow-up. After the follow-up period, all data were analysed using the Statview 4.5 statistical package for Windows. Survival analysis was performed using Cox proportional hazard method for continuous variables [25]. For nominal variables, Kaplan–Meier survival curves were drawn. Multivariate analysis was then performed to identify mutually independent predictors of survival. A P-value of less than 0.05 was considered to be statistically significant. Receivers operating characteristic curves were drawn to show

the trendoff between sensitivity and specificity predicting mortality.

3. Results Of the 241 CHF patients who were analysed (mean follow-up period, 31618 months), 75 patients died after 0.4 to 56 months (mean, 14613 months; median, 12 months). The mean follow-up period of the 166 survivors was 39613 months; (range, 2.6–61 months; median, 36 months). The cumulative survival of all patients was 88% at six months (95% CI, 7.6–16.0), 84% at 12 months (95% CI, 10.5–20.1), 76% at 24 months (95% CI, 18.2–29.4), and 70% at 36 months (95% CI, 23.1–35.5). The primary end point was all-cause mortality. Tables 2 and 3 give clinical details of the CHF patients with three groups

Table 3 Comparisons by peak oxygen consumption, left ventricular ejection fraction and by IVCD groups

Age (years) Height Weight BMI a Peak VO 2 b LVEF d IVCD e QTc f Plasma Na 1 c a

Comparison by peak VO 2 b ml / kg / min

Comparison by LVEF d

Comparison by IVCD e groups

,14 (n565)

.14 (n5160)

,25% (n585)

.25% (n594)

,120 ms (n5149)

120–160 ms (n552)

.160 ms (n540)

63 (9) 171 (8) 76 (14) 26 (5) 10.9 (2.2) 23 (13) 136 (35) 463 (57) 137.5 (3.5)

58 (11) 173 (8) 80 (15) 26 (4) 20.6 (6.0) 30 (14) 116 (30) 440 (47) 138.6 (2.8)

58 (10) 172 (8) 78 (15) 26 (4) 16.5 (6.6) 16 (6) 133 (34) 457 (52) 138.1 (3.3)

61 (12) 172 (8) 81 (15) 27 (4) 18.7 (6.3) 39 (10) 115 (30) 437 (51) 138.5 (2.9)

57 (11) 172 (9) 81 (14) 27 (4) 19.2 (6.9) 31 (15) 100 (12) 426 (40) 139.2 (3.0)

63 (10) 172 (8) 78 (15) 26 (4) 15.5 (6.2) 25 (12) 139 (12) 452 (37) 138.3 (3.5)

63 (8) 173 (8) 74 (13) 24 (4) 15.3 (6.0) 22 (11) 181 (13) 508 (57) 137.6 (2.8)

Body mass index, b peak oxygen consumption, c sodium, d left ventricular ejection fraction, e intraventricular conduction delay, f corrected Qt interval.

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Table 4 Univariate analysis-predictors of mortality in patients with CHF (Cox proportional hazard) Variable

P (likelihood ratio test)

Hazard ratio (95% CI)

Age MVO 2 a LVEF b Na 1 c IVCD d PRe QT f QTc g R–R interval HRh Mean BP NYHA III and IV

0.003 ,0.0001 ,0.0001 0.015 ,0.0001 0.93 0.04 ,0.0001 0.1 0.13 ,0.0001 ,0.0001

1.033 (1.011–1.056) 0.852 (0.807– 0.900) 0.949 (0.927–0.972) 0.911 (0.846–0.982) 1.017 (1.011–1.024) 1.00 (0.991–1.008) 1.004 (1.000–1.009) 1.012 (1.006–1.017) 1.002 (0.999–1.005) 1.011 (0.996–1.026) 0.962 (0.945–0.978) 2.817 (1.709–4.642)

months respectively (95% CI for 36-months mortality, 50–78). Of the 37 patients with an IVCD of greater than 160 ms, 58.3% (19) had died at 36 months (95% CI for 36-months mortality, 38–78). Of the 65 patients with a peak VO 2 of less than 14 ml / kg / min, 62.5% (40) had died at 36 months (95% CI for 36-months mortality, 50–74). The detailed results for the predictors of mortality are given in Table 4 and the results of multivariate analyses are given in Table 5. Peak oxygen consumption, NYHA Class III or IV, IVCD, and left ventricu-

a

Peak oxygen consumption, b left ventricular ejection fraction, c plasma sodium, d intraventricular conduction delay, e PR interval, f QT interval, g corrected QT interval, h heart rate.

of IVCD (,120 ms, 120–160 ms, .160 ms) survivors and non-survivors, and patients with peak oxygen consumption ,14 and $14 ml / kg / min. Of the 141 patients with IVCD values of less than 120 ms, 20% (27) had died at 36 months (95% CI for 36-months mortality, 13–27). Of the 52 patients with IVCD of 120–160 ms, 36% (18) had died at 36 Table 5 Multivariate analysis-predictors of mortality in patients with CHF (Cox proportional hazard) Variable

P (Likelihood ratio test)

Hazard ratio (95% CI)

IVCD MVO 2 b

0.0002 ,0.0001

1.013 (1.006–1.020) 0.865 (0.818–0.914)

IVCD Age

,0.0001 0.03

1.016 (1.009–1.023) 1.025 (1.002–1.049)

IVCD LVEF c

0.001 0.0002

1.012 (1.005–1.019) 0.955 (0.932–0.978)

IVCD Na 1

,0.0001 0.08

1.016 (1.010–1.023) 0.927 (0.852–1.009)

IVCD Mean BP d

,0.0001 0.0002

1.015 (1.009–1.021) 0.966 (0.948–0.984)

0.001 0.08

1.013 (1.005–1.021) 1.006 (0.999–1.012)

a

IVCD QTc a

IVCD plus MVO 2 plus LVEF IVCD 0.012 MVO 2 0.0001 LVEF 0.001 a

1.010 (1.002–1.017) 0.887 (0.835–0.943) 0.961 (0.939–0.984)

Intraventricular conduction delay, b peak oxygen consumption, c left ventricular ejection fraction, e corrected QT interval, f blood pressure.

Fig. 1. Graded increase in mortality with increasing intraventricular conduction delay (IVCD).

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lar ejection fraction were significant predictors of mortality. In addition, the continuous variable of peak oxygen consumption (P,0.0001), hazard ratio 0.85 [95% CI, 0.80–0.90] predicted mortality. Fig. 1 shows that there is a graded increase in mortality with an increase in the IVCD. As the value of IVCD increases, so does mortality. This is not seen in the case of QTc. Patients were then divided into three groups for IVCD (IVCD,120 ms, IVCD 120–160 ms and IVCD.160 ms), and for QTc (QTc,420 ms, QTc 420–460 ms and QTc.460 ms). In Kaplan– Meier survival analyses (Fig. 2), IVCD predicted prognosis better than QTc. Receiver operating characteristic curves (Fig. 3) were drawn to demonstrate the tradeoff between sensitivity and specificity for predicting mortality. The area under the curve is a measure of the overall ability of the test to predict mortality. The area under the curve for IVCD is 0.73 and for QTc, it is 0.65. Bivariate analyses revealed that the IVCD had significant prognostic power independent of each of the following continuous variables: age, mean blood pressure, left ventricular ejection fraction, peak oxygen consumption and plasma sodium concentration (Table 5). Conversely, apart from plasma sodium and age, all of these variables were significant predictors

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of mortality independently of the presence of prolonged IVCD. We formed a multivariate model that included LVEF, IVCD and peak oxygen consumption, which showed that all three variables were independent predictors of mortality (Table 5). The patient’s age did not contribute independent prognostic value to this model. Interestingly, separating patients according to NYHA functional class (I / II versus III / IV), added as a dichotomous covariate, also failed to provide extra prognostic information [NYHA Class III / IV: P5 0.62; 1.15 (0.63–2.1)]. Only peak oxygen consumption (P50.0005), hazard ratio [0.89 (0.83–0.95)], left ventricular ejection fraction [P50.0012; 0.96 (0.93– 0.98)], and IVCD [P50.012; 1.01 (1.00–1.01)] predicted mortality.

4. Discussion The present study has demonstrated that the electrocardiogram could provide independent prognostic information in patients with CHF. This study shows that IVCD is a better prognostic marker than other conventional ECG values. There is a stepwise in-

Fig. 2. Comparison by different cut-off values of intraventricular conduction delay (IVCD) and corrected QT interval (QTc) for predicting survival, using Kaplan–Meier survival curves.

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Fig. 3. Comparison by sensitivity and specificity of intraventricular conduction delay (IVCD) and corrected QT interval (QTc) for predicting survival, using receiver operating characteristic curves.

crease in mortality as a graded increase in the duration of IVCD occurs. There is no evidence of any threshold effect at an IVCD of 120 ms. The cause of

this graded effect of IVCD on mortality may be due to interstitial fibrosis, myocyte cell death or an increase in the chamber size [26,27].

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Impaired prognosis is one of the major features of the clinical syndrome of heart failure. Prognostic markers in CHF patients have been shown to include changes in the ECG. The most commonly reported abnormalities were those of QRS complex morphology, which includes pathological Q waves, ventricular hypertrophy and bundle branch block, and T wave morphology [19]. If multiple ECG criteria are utilised at the time of diagnosis, they may be helpful for risk factor characterisation [28]. However, a number of questions remained unanswered. In particular, it is widely assumed that once the QRS duration has reached 120 ms, complete bundle branch has occurred [29], so that any relation between QRS duration values greater than this and prognosis has attracted less attention. We investigated the importance of actual duration of IVCD in CHF. These electrocardiographic predictors have advantages over the other haemodynamic parameters of prognosis in heart failure in that they are relatively independent from the loading conditions or inotropic states and are usually not affected by short-term treatment. Intraventricular conduction disturbances have been widely recognised as a prognostic marker in patients with heart failure [3,30–33]. The limitation with most of these studies is that they included only relatively small numbers of patients and in one study where IVCD was studied, the authors considered only the presence or absence of intraventricular conduction delay, rather than the values of IVCD [34,35]. Our multivariate model, which included LVEF, IVCD and peak oxygen consumption, showed that all three variables were independent predictors of mortality. Other parameters of cardiopulmonary exercise testing were important predictors of survival. We also investigated the percentage achieved of predicted peak oxygen uptake (% VO 2 ), which does not provide additional predictive information to the peak oxygen consumption value, and it is consistent with a recent study [36]. Although this is a retrospective study, it has assessed an extensive group of patients with CHF and included all that fulfilled relatively broad criteria. The patients themselves were to some extent selected in having been referred and followed up in a heart failure clinic. QTc was measured in a single lead in each patient,

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and dispersion between the leads was not assessed. This was because we concentrated on parameters that the general physicians or family physicians frequently have available in their surgeries or clinics. The cause of death in individual cases was not determined, as it is seldom certain that such differentiation is reliable. As mentioned before, a clear distinction between sudden death and death from progressive heart failure is not always possible. As was done recently in a prospective study [37], our study was not designed to analyse the mode of death. We therefore performed the present analysis for total death, and a separate analysis for sudden death and death from heart failure was not conducted.

5. Conclusion This study suggests that intraventricular conduction delay is the most powerful prognostic predictor amongst the simple ECG parameters in patients with CHF. QTc is also a significant prognostic indicator, whose predictive power is only slightly less. The graded increase in the duration of IVCD is associated with a graded increase in the mortality, with no threshold at 120 ms.

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