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European Journal of Heart Failure 2005 7(2):269-275; doi:10.1016/j.ejheart.2004.10.016
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© 2005 European Society of Cardiology

QT dynamicity: a prognostic factor for sudden cardiac death in chronic heart failure

Atul Pathaka,b,*,1, Daniel Curnierc,d,1, Joëlle Fourcadeb, Jéme Roncallia,b, Phyllis K. Steine, Patricia Hermantb, Marc Bousquetd, Pierre Massabuaub, Jean-Michel Sénarda, Jean-Louis Montastruca and Michel Galiniera,b

a CESNA (Club d'Etude du Systrme Nerveux Autonome) et INSERM U586, Laboratoire de Pharmacologie médicale et clinique, Faculté de Médecine 37 allés Jules Guesde, 31073 Toulouse Cedex, France
b Fédération des Services de Cardiologie, Centre Hospitalier Universitaire de Rangueil 1 avenue Jean Poulhès, 31403 Toulouse, France
c Unité de Formation et de Recherche en Sciences et Techniques des Activités Physiques et Sportives (UFRSTAPS), Université Paul Sabatier 118 route de Narbonne, 31062 Toulouse Cedex 4, France
d Clinique de réadaptation cardio-vasculaire et pulmonaire de St Orens 12 avenue de Revel, 31650 St Orens, France
e Heart Rate Variability Laboratory, Cardiovascular Division, Washington University School of Medicine USA

* Corresponding author. Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 37 allés Jules Guesde, 31073 Toulouse Cedex, France. Tel.: +33 5 61 14 59 64; fax: +33 5 61 25 51 12. E-mail address: pathak{at}cict.fr


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Introduction: The aim of this study was to determine whether impaired adaptation of the QT interval to changes in heart rate predicts sudden death in patients with chronic heart failure (CHF).

Methods: We prospectively included 175 CHF patients in sinus rhythm. QT dynamicity was evaluated by analyzing 24-h Holter recordings. The linear regression slope of QT interval measured to the apex and to the end of T wave plotted against RR intervals was calculated using a dedicated Holter algorithm.

Results: Mean follow-up was 29.9±17.9 months. There were 48 deaths, of which 21 were sudden. The actuarial 3-year mortality rates were 38.4% for overall mortality and 14.1% for sudden death. Of all the parameters, an increased QTe/RR slope (>0.28) was the strongest independent predictor of sudden death (relative risk 3.47, 95% confidence interval 1.43–8.40, p=0.006).

Conclusion: Increased 24-h QTe dynamicity is independently predictive of sudden death among patients with heart failure. This simple parameter may help to stratify risk and select patients who may benefit from antiarrhythmic prophylaxis.

Received June 25, 2004; Revised September 27, 2004; Accepted October 20, 2004


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Various experimental and clinical studies have demonstrated that the autonomic nervous system (ANS) plays a critical role in arrhythmic sudden death [1]. Sympathetic overactivity increases the risk of ventricular arrhythmias while increased parasympathetic activity protects from ventricular fibrillation. Different markers of autonomic nervous system function such as heart rate variability (HRV) [2] and baroreflex sensitivity, have been found to be useful risk stratifiers in chronic heart failure (CHF) patients. Parameters measuring ventricular repolarization such as QT dispersion [4], QT dynamics [3] and QT interval rate dependence have been studied in heart failure patients, and have also shown to be a reliable predictor of arrhythmic events or death in chronic heart failure [4]. However, most studies using noninvasive testing have failed to discriminate between patients with sudden cardiac death and patients dying from other causes. Most of these markers reflect the effect of sympathovagal imbalance on the sinus node but do not provide information on the effect of autonomic imbalance on the myocyte per se. Other possible limitations of QT interval-related measurement are the lack of a uniformly accepted definition for the end of the QT interval on manually read EKGs [5] and the influence of both heart rate and the ANS influence on the QT interval. Abnormal rate adaptation of ventricular repolarization, known as QT dynamicity (measured by the slope of linear regression of QT/RR), may serve as such a marker. Abnormal QT dynamicity has been described in patients who are prone to ventricular arrhythmias [6–9]. The QT/RR relationship can be measured with commercially available software but has never been investigated as an index of ventricular arrhythmogenicity or of sudden cardiac death in a large population of heart failure patients.

We conducted this prospective study to determine the prognostic value for all-cause mortality and sudden cardiac death of QT dynamicity parameters in a population of ambulatory patients with moderate to severe chronic heart failure.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
From January 1996 to October 2000, 175 consecutive patients with chronic heart failure were prospectively enrolled in this study. The patients gave informed consent, and the study was approved by the ethics committee of our institution. All patients were in sinus rhythm and in New York Heart Association (NYHA) classes II–III with a left ventricular ejection fraction ≤45%. They were clinically stable for at least 2 weeks. This study population consisted mainly of patients referred to our center for follow up or heart failure evaluation, without history of syncope or cardiac arrest. Investigations included clinical examination, routine biochemistry, 12-lead electrocardiography, two-dimensional Doppler echocardiography and 24-h ambulatory Holter EKG. Patients with a history of valvular heart disease, atrial fibrillation, electrolyte imbalance, diabetes (defined by fasting glucose >7.78 mmol l–1), recent myocardial infarction or unstable angina were excluded from this study. The diagnosis of dilated cardiomyopathy was based on the presence of a depressed left ventricular ejection fraction with an absence of significant coronary artery disease or other specific heart muscle disease [10].

2.2. 24-h EKG Holter recording: QT dynamicity and HRV parameters
Patients admitted with heart failure had 24-h ambulatory ECG recordings with two bipolar ECG leads. The recordings were performed at a 200-Hz sampling rate. The ELATEC Holter analysis QT software (ELA Medical, Montrouge, France) was used for analysis. Recordings were excluded if they lasted <20 h, if they were of poor quality, if atrial fibrillation or a paced rhythm was present or if T wave amplitude was <0.15 mV. The 24-h EKG Holter data were converted into 2880 templates obtained at 30-s intervals. Only intervals in which >80% of QRS complexes were eligible were included. For each template, average QT intervals were measured automatically from the onset of the Q wave to the apex of the T wave (QTa) and to the end of the T wave (QTe). The apex of the T wave was calculated by fitting a parabola through the peak of the T wave. The intersection of the tangent of the downslope with the isoelectric baseline was used for the QT measurement algorithm. The QTa and QTe intervals were correlated with the mean cycle length of the 30-s interval. The slope of QT/RR plots of the linear regression were calculated automatically for both QTa and QTe and for the entire 24 h, daytime (9 a.m.–9 p.m.) and nighttime (11 p.m.–6 a.m.). The mean QT end (QTe) and QT apex (QTa) of each period were plotted against the mean RR and linear regressions (y=ax+b) were calculated (QTe/RR and QTa/RR) with QT slope (a) and QT y intercept (b). This step allowed the quantification of QT dynamics. We then applied a RR of 800 ms to the previous QT/RR regression formulas to obtain QT at an identical HR (QTe 800 or QTa 800). QT interval rate dependence was calculated using the following formula: QT night minus QT day at a fixed RR interval of 800 ms. The calculations were done at the apex (delta QTa) and the end of the T waves (delta QTe).

Time domain HRV was analyzed and the following indexes calculated [11]: SDNN, SDANN, SDNNIDX (SDNN index) and rMSSD. Spectral analysis was performed over 256-s periods. The computation was done only if there were more than 100 normal beats and 80% normal complexes within the 256 s. As a 50% overlapping function was applied on the 256-s buffer, the analysis was computed every 128 s and the spectra were averaged. The 256-s tachograms were sampled at a 4-Hz frequency to obtain equi-distant sampling. A Hanning window was applied to reduce the leakage error. All the parameters were computed from normal-to-normal RR values (QRS complexes of sinus origin) and determined for 24 h. The power spectral density of the pre-processed signal was computed and the results expressed in natural logarithm of square of milliseconds per Hz. The areas under the spectral density curve between the limits of the spectral bands of high and low frequency were then integrated to obtain values for high and low frequency power.

2.3. Follow-up
Follow-up data were obtained by reviewing medical records. Surviving patients were identified by direct examination or from patients' general practitioners. Cause of death was determined from hospital records or by direct communication with patients' general practitioners or families. Every effort was made to discriminate between pump failure and sudden cardiac death, defined as death occurring within 1 h of onset of symptoms in a previously medically stable patient, death during sleep, or unwitnessed death (occurring within 1 h of the patient last being seen alive). Deaths related to sustained ventricular tachycardia or resuscitated ventricular fibrillation were classified as sudden cardiac death. Cardiac transplantation was considered an end point for the follow up.

2.4. Statistical analysis
Quantitative data were expressed as mean±standard deviation (S.D.). The association of each of the baseline patient characteristics (Tables 1 and 2) with survival was assessed using a Cox proportional hazards model. Survival time estimates were calculated by the method of Kaplan–Meier. Statistical comparisons between survival curves were done using the log-rank test. Statistical significance was p<0.05. Multivariate survival analysis was performed using a Cox proportional hazards model to determine which factors were significantly associated with all cause mortality after adjustment for the other variables. Variables selected to be tested in stepwise multivariable analysis were those with a p<0.10 in the univariate model. The stepwise selection was done using a p to remove from and a p to enter into the model ≤0.05 with both prior backward selection after inclusion of all the selected variables (saturated model) and then forward selection. Results are presented as relative risk with confidence intervals (CI 95%) and p-values (computed with STATVIEW® 5.0).


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  		Table 1 Clinical characteristics and treatment in 175 patients with chronic heart failure

 


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  		Table 2 Characteristics of heart rate variability and QT dynamics parameters in 175 chronic heart failure patients

 

   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Patient characteristics
The study population consisted of 175 consecutive patients, 150 men and 25 women, mean age 56.3±12.7. The etiologies of chronic heart failure were ischemic heart disease in 75 patients and idiopathic dilated cardiomyopathy in 100 patients. The clinical characteristics of the patients are summarized in Table 1. Characteristics of heart rate variability and QT dynamics are presented in Table 2.

3.2. Follow-up data
During the mean follow-up of 29.9±17.9 months, 48 patients died. Sudden cardiac death occurred in 21 patients. The 3-year mortality rate was 32.6%. Five patients received heart transplants.

3.3. Univariate predictors of total mortality and sudden death
As can be seen in Table 3, significant univariate predictors of total mortality were: increased age (p<0.0001), NYHA class III vs. II (p=0.0022), presence of A-V block (p=0.0356), increased cardiothoracic ratio (p=0.0105), Na<135 mEq (p=0.0143), creatinine>119 mmol (p=0.0022), digoxin treatment (p=0.0303), decreased total power (p<0.0001), low frequency power (p<0.0001), high frequency power (p=0.0245), SDNNIDX (p=0.0049), SDNN (p<0.0001) or SDANN (p=0.0003) and a 24-h QTe/RR slope >0.28 (p=0.0259).


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  		Table 3 Overall mortality in relation to clinical, heart rate variability and QT dynamics measures-univariate and multivariate Cox proportional hazards survival analysis (n=175, 48 deaths)

 
Upon univariate analysis, significant predictors of sudden death (Table 4) were: increased age (p=0.025), decreased LVEF (p=0.001), ischemic cardiomyopathy (p=0.009), increased cardiothoracic ratio (p=0.035), decreased ln total power (p=0.009), ln high frequency power (p=0.044), ln low frequency power (p=0.007) or SDNN (p=0.016), Na<135 mEq (p<0.001), increased creatinine (p=0.016), digoxin use (p=0.031), a 24 h QTe/RR slope 24-h >0.28 (p=0.008) and a QTe y intercept 24-h <190 ms (p=0.004).


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  		Table 4 Sudden death in relation to clinical, heart rate variability and QT dynamics measures-univariate and multivariate Cox proportional hazards survival analysis (n=175, 21 deaths)

 
Slopes of QT/RR were divided into quartiles for each time period. Of the QT dynamicity parameters, an increased 24-h QTe/RR slope >0.28 (compared to the first three quartiles grouped together) was the most predictive of sudden death [relative risk (RR) 3.0, confidence interval (CI) 1.27–7.09, p<0.0083] and of total mortality [RR 2.2, CI 1.24–3.9, p<0.0055] (Table 3 and 4Go). QTa dynamicity parameters were not associated with outcome.

3.4. Multivariable analysis for total mortality and for sudden death
Table 3 shows result of the multivariate Cox regression analysis for total mortality. Increased age (p<0.001), NYHA III (p=0.022) and decreased SDNN (p=0.004) were retained as independent predictors of mortality. Table 4 shows results of multivariate analysis for prediction of sudden death. Increased age (p=0.021), digoxin treatment (p=0.007), increased cardiothoracic ratio (p=0.001), increased creatinine (p<0.001) and QTe slope (24 h) >0.28 (p=0.006) were retained as independent predictors of sudden death. There was no independent association between presence of A-V block or left bundle branch block and mortality. This factor was then tested as stratification variable in all previous models. There were no differences in the results.

The hazard ratio of 24-h QTe dynamicity was more than 50% higher for sudden death than for mortality from all causes [RR 3.4, CI 1.43–8.40 vs. RR 2.2, CI 1.24–3.9, respectively].


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
In this long-term follow-up study of CHF patients, we found that an increased 24-h rate dependency of ventricular repolarization (otherwise known as QT dynamicity) was a strong independent predictor of sudden death.

Dynamicity of the QT interval is a surrogate of action potential physiology at the cellular level. It reflects the influence of various factors such as heart rate, sympathovagal balance, drugs and metabolic state on the myocyte [12]. QT dynamicity refers to the flexibility of the QT interval. A steeper QTe/RR slope indicates that the QT interval prolongs more with longer RR intervals [13,14]. This suggests that repolarization, in the setting of CHF, is more labile, thereby increasing patients vulnerability to development of malignant reentry arrhythmias. Increased QT dynamicity was also found in a study in post MI patients in which subjects with previous ventricular tachycardia had a greater QT/RR slope than those without [15] and in post MI patients where it was the most predictive parameter of sudden death [8].

Increased QT/RR slope in the setting of CHF supports the major role of the sympathetic nervous system in the modulation of QT dynamics and arrhythmia genesis. β blockade has been shown to reduce the QT/RR slope [7,16]. In isolated canine myocytes, isoproterenol prolongs action potential duration at low concentrations but shortens it at high concentrations [17]; thus, β-blockers may reduce action potential prolongation during low sympathetic tone (at slow heart rates) and reduce action potential shortening at fast heart rates. Short action potential durations are proarrhythmic, as short refractory periods facilitate reentry. This mechanism may explain, at least in part, the reduction in mortality and arrhythmic sudden death in trials with CHF patients taking β-blockers [18].

Importantly, the prognostic information of QT dynamicity parameters was found in the terminal portion of the QT interval (QTe). Behaviour of the QTa/RR slope did not predict survival, a finding inconsistent with a study comparing 51 post-MI patients who died of cardiac causes with 51 matched survivors [19]. In another study, Merri et al. [13] showed that among several variables of repolarization in normal subjects, only the duration of the S wave to the T wave apex is rate dependent and that the interval of the T wave apex-to-the end is rate independent. One can hypothesize that the T wave apex-to-the end interval is influenced by factors other than rate, such as autonomic tone.

Yan and Antzelevitch [20] have suggested that the apex of T wave is synchronous with epicardial repolarization, whereas the end of the T wave provides information on the cells that are the last to repolarize. It has been shown that cells across the myocardium do not share the same electrophysiological properties. For instance, the M cells [21], which reside in the deep layer of the myocardium, are characterized by their ability to prolong their action potential more than that of other ventricular cells in response to a slowing of rate or to agents that prolong action potential duration [22]. Thus, QTe unlike QTa may yield information on the physiology of those cells, which are thought to play an important part in ventricular arrhythmogenesis.

It has been shown that, due to differing autonomic influences, QT dyamicity is greater during the day than at night [23,12,24]. In our study, only 24-h QTe dynamicity was predictive of events. This suggests that QTe/RR modifications are not under the influence of the sympathovagal balance and that this parameter primarily characterizes the state of myocytes in the setting of chronic heart failure.

In contrast with QT dynamicity, QT rate dependence was not significantly related to mortality or sudden cardiac death in univariate or multivariate analysis. The difference in QT/RR slope (delta QT) between day and nighttime at the same heart rate was similar to the low values found in the literature with patients having various type of dysautonomia (heart transplant patients [25] or patients with diabetic neuropathy [26]). In all of these cases, decreased QT interval rate dependence was related to sympathovagal modifications. In our study, even though QT interval rate dependence was reduced, this parameter was not a prognostic marker for cardiac events.

Depressed HRV is known to predict arrhythmic event as overall mortality in patients with various diseases among them CHF [27,28]. In our study, SDNN and SDANN were both predictors of overall mortality and SCD in univariate analysis. However, only SDNN was still predictive of overall mortality in multivariate analysis. Our data shows that SDNN is more predictive than QT dynamicity for overall mortality, while QT dynamicity appears to have more power to identify CHF patients at risk for SCD. These data suggest that among 24-h Holter-derived EKG parameters, HRV and QT dynamicity parameters are complimentary for screening of CHF patients at high risk of mortality or SCD.

4.1. Limitations of the study
One limitation of this study was the necessity of recruiting patients in sinus rhythm thus eliminating subjects with atrial fibrillation, which is prevalent among CHF patients. Moreover, we also excluded patients with valvular heart disease or diabetes, which are common features associated with CHF. We therefore suggest that further studies are warranted, in a broader range of CHF patients, to extrapolate our findings into general practice. In our study, the prevalence of DCM was greater than is usually seen in cohort studies of heart failure patients. This may be explained by the fact that we are a referral center for CHF in the southern part of France, and simple cases of IHD are usually managed in primary centers. However, it is known that patients with IHD have a lower survival rate than patients with DCM [29]; thus, our results probably underestimate the prognostic value of QT dynamicity. The rate of use of β-blockers was relatively low in this study because patients were recruited at a time when β-blockers were just beginning to be used in CHF. However, a recent study has established that the rate of use of β-blockers in non-trial participants was 34%, which is a similar rate to our study [30]. It is possible that, had the rate of v-blocker use been higher, results might have been different. However, there was no significant difference in QT/RR slopes between patients with and without β-blockers. Moreover, the influence of spironolactone or digoxin on dynamic ventricular repolarisation are also unknown. This limitation is of importance, since both drugs have been shown to influence outcome of CHF patients, particularly as regards sudden cardiac death.

The presence of a true linear relationship between QT and RR intervals may be questioned; however, correlation coefficients for linear regression slopes in our patients were good (0.94±0.06 for QTa/RR and 0.89±0.04 for QTe/RR). Furthermore, it can be argued that an increased QT/RR slope may somehow be linked to higher heart rates, thought to be associated with increased mortality. However, in our study, increased heart rate was not independently associated with mortality or sudden cardiac death.


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The limited availability of automatic defibrillators, a highly efficient treatment for preventing SCD in CHF patients, because of limited economic resources stresses the need for specific markers to identify patients at high risk for malignant ventricular arrhythmia. Early screening for this risk should use simple, accurate and inexpensive tools. The data from our study strongly support abnormal 24-h QTe dynamicity as a risk stratifier for sudden death in CHF patients. With the advent of digital Holter recording, we currently are well equipped to study this parameter, which is applicable to clinical practice. However, the growing number of prognostic factors in CHF patients stresses the need to develop a prognostic score and a risk stratification algorithm taking into account relevant prognostic factors to identify CHF patients at higher risk for sudden cardiac death. Additional studies are thus needed to investigate whether abnormal QT/RR physiology would allow us to screen for the right antiarrhythmic therapy with the aim of improving outcome in CHF patients.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
1 Daniel Curnier and Atul Pathak both contributed equally to this work. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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R. Due-Andersen, T. Hoi-Hansen, C. E. Larroude, N. V. Olsen, J. K. Kanters, F. Boomsma, U. Pedersen-Bjergaard, and B. Thorsteinsson
Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity
Europace, July 1, 2008; 10(7): 860 - 867.
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Home page
 EuropaceHome page
R. Due-Andersen, T. Hoi-Hansen, N. V. Olsen, C. E. Larroude, J. K. Kanters, F. Boomsma, U. Pedersen-Bjergaard, and B. Thorsteinsson
Cardiac repolarization during hypoglycaemia and hypoxaemia in healthy males: impact of renin-angiotensin system activity
Europace, February 1, 2008; 10(2): 219 - 226.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
M. Iacoviello, C. Forleo, P. Guida, R. Romito, A. Sorgente, S. Sorrentino, S. Catucci, F. Mastropasqua, and M. Pitzalis
Ventricular Repolarization Dynamicity Provides Independent Prognostic Information Toward Major Arrhythmic Events in Patients With Idiopathic Dilated Cardiomyopathy
J. Am. Coll. Cardiol., July 17, 2007; 50(3): 225 - 231.
[Abstract] [Full Text] [PDF]

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