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European Journal of Heart Failure 2001 3(6):717-721; doi:10.1016/S1388-9842(01)00191-X
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© 2001 European Society of Cardiology

The effects of chronic carvedilol therapy on QT dispersion in patients with congestive heart failure

Aylin Yildirir*, Elif Sade, Lale Tokgozoglu and Ali Oto

Hacettepe University School of Medicine, Department of Cardiology Ankara, Turkey

* Corresponding author. Simon Bolivar Cad. No: 18/34 06550 Cankaya, Ankara, Turkey; Tel.: +90-312-440-9033; fax: +90-312-441-3553. E-mail address: ayliny{at}ato.org.tr (A. Yildirir).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Carvedilol therapy reduces mortality from sudden cardiac death and progressive pump failure in congestive heart failure (CHF). However, the effect(s) of carvedilol on ventricular repolarization characteristics is unclear.

Aim: The aim of the study was to investigate the effects of chronic carvedilol therapy on ventricular repolarization characteristics as assessed by QT dispersion (QTd) in patients with CHF.

Method: Nineteen patients (age 53±12 years; 16 male, three female) with CHF (eight ischemic, 11 non-ischemic dilated cardiomyopathy) were prospectively included in the study. Carvedilol was administered in addition to standard therapy for CHF at a dose of 3.125 mg bid and uptitrated biweekly to the maximum tolerated dose. From standard 12-lead electrocardiograms the maximum and minimum QT intervals (QTmax, QTmin), QTd, corrected QT intervals (QTcmax, QTcmin) and corrected QTd (QTcd) values were calculated at baseline, after the 2nd and the 16th month of carvedilol therapy.

Results: A significant reduction was noted in the QTd and QTcd values with carvedilol therapy after the 16th month (QTd: 81±22 ms vs. 40±4.3 ms P<0.001; QTcd: 91±25 ms vs. 51±7 ms P<0.001), but not after the 2nd month (P>0.05). The resting heart rate was also significantly reduced after a 16-month course of carvedilol therapy (78±13 bpm vs. 66±15 bpm, P<0.05). Carvedilol therapy did not alter QTmax and QTcmax intervals (P>0.05), however, QT min and QTcmin significantly increased with carvedilol at the 16th month (P<0.001 and P<0.01, respectively).

Conclusion: Long-term carvedilol therapy was associated with a reduction in QTd, an effect that might contribute to the favorable effects of carvedilol in reducing sudden cardiac death in CHF.

Key Words: Carvedilol • QT dispersion • Congestive heart failure

Received November 16, 2000; Revised March 12, 2001; Accepted May 9, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Ventricular arrhythmias and sudden cardiac death are not uncommon problems in patients with congestive heart failure (CHF) [1]. Thirty-five to 45% of the patients with CHF die suddenly without any evidence of hemodynamic or functional deterioration, presumably as a consequence of lethal ventricular arrhythmias [1–4]. Carvedilol, a new generation beta-adrenergic antagonist with alpha-adrenergic receptor blocking effect, has been shown to reduce mortality by 65% in CHF patients compared to a placebo [5]. The benefit derived from carvedilol therapy is unclear, but most likely to be mediated by both slowing of the progression of heart failure and reduction of sudden cardiac death.

Clinical and electrophysiological studies have shown the importance of inhomogeneous myocardial repolarization characteristics in the genesis of ventricular arrhythmias [6]. QT dispersion (QTd) in the 12-lead electrocardiogram (ECG) reflects regional differences in myocardial repolarization and provides indirect information of arrhythmogenicity [7]. Increased QTd and corrected QTd (QTcd) values have been reported in patients with CHF compared to controls, and are considered as potential markers for predicting drug effects on mortality [8,9]. A number of studies have examined the effect of several drugs in QTd [10–13], however, there are very limited data relating to the effects of carvedilol. Therefore, in this study we aimed to investigate the effect of chronic carvedilol therapy on QTd in patients with CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
Patients admitted to the Department of Cardiology of our institution with a diagnosis of CHF were screened and 19 of them who satisfied the inclusion and exclusion criteria were enrolled. The inclusion criteria were the presence of: NYHA Class II–IV CHF; ejection fraction less than 40%; and the current treatment for CHF with standard therapy including: diuretics; angiotensin converting enzyme (ACE) inhibitors; digoxin; hydralazine; and/or nitrates at a stable dosage for at least 2 weeks. Patients with: uncorrected primary obstructive or severe regurgitative valvular disease; restrictive or hyperthrophic cardiomyopathy; uncontrolled ventricular arrhythmias; chronic obstructive pulmonary disease; brittle diabetes; unstable angina; or active myocarditis were excluded. Patients with: sick sinus syndrome; second or third degree heart block; bradycardia (<60 bpm); and hypotension (<90 mmHg) were also not considered for carvedilol therapy.

The initial dose of carvedilol was 3.125 mg bid, which was doubled at 2-weekly intervals as tolerated up to 25 mg bid. Patients were continued on their conventional CHF treatment in addition to carvedilol. All patients had standard ECG recordings obtained at the same paper speed and gain setting (25 mm/ms and 10 mm/mV, respectively) before treatment and at the end of the 2nd and 16th months. The fractional shortening from M mode echocardiographic studies was measured in the same schedule by an experienced cardiologist as a systolic function parameter. The serum levels of electrolytes were evaluated at regular intervals.

All ECGs were evaluated manually by a single observer, blinded to the clinical status of the patient. QT interval was measured from the beginning of the QRS complex to the end of the T wave, defined as the return to T–P baseline. When U waves were present, the QT interval was measured to the nadir of the curve between the T and U waves. QT intervals were measured in all leads if technically possible. For each lead two or three consecutive cycles were measured and the arithmetic mean of the QT interval for that lead was used in all future calculations for QTd. QT dispersion was defined as the difference between the maximum and minimum measured QT intervals (QTmax and QTmin) across the 12-lead ECG. The measured values were than expressed as both uncorrected and rate corrected QT intervals and QTd, using Bazett's formula (QTc:QT/square root of RR interval). Data were expressed as mean±S.D. Statistical analysis was performed using T-test and Wilcoxon test for paired samples. A value of P<0.05 was considered significant.

This investigation conforms to the principles outlined in the Declaration of Helsinki. Permission from the local ethics committee was obtained and each patient gave written informed consent.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Of the 19 patients included in the study eight had ischemic (42%) and 11 (58%) had non-ischemic dilated cardiomyopathy as the underlying cause for CHF. The mean age of the study group was 53±12 years (range 35–73) and 16 of them (84%) were male. Eleven patients (58%) were Class II and eight patients (42%) were Class III depending on the NYHA Classification. The duration of the disease was a minimum of 2 years from the diagnosis of CHF and during this period all subjects were on standard treatment including: digoxin (68%); diuretic (53%); nitrate (37%); and ACE inhibitors (74%). The serum levels of potassium and magnesium remained the same at baseline and during follow-up. Of the 19 patients, 14 completed the study; carvedilol was discontinued in three patients due to the worsening of CHF after the first doses or the need to administer another class of drug incompatible with carvedilol. One of our patients died suddenly at the 4th week and the other had the new diagnosis of malignancy.

The QTd and QTcd values at baseline, and after 2 and 16 months of carvedilol therapy are summarized in Table 1. The mean baseline QTd was 81±22 ms, which was higher than that seen in normal individuals (between 20 and 50 ms) [14]. The QTd and QTcd were not significantly altered with carvedilol treatment during the first 2 months (P>0.05). However, significant reductions were noted in QTd and QTcd values at the end of the 16th month (both P<0.001). The QTmax and QTcmax values tended to be constant throughout the follow-up period (P>0.05), while QTmin significantly increased from 335±39 to 387±33 ms at the 16th month (P<0.001). The increase in the QTcmin was significant since the 2nd month (P<0.05 at the 2nd month and P<0.01 at the 16th month). The mean heart rate, which was 78±13 bpm at baseline, significantly decreased to 66±15 bpm at the 16th month of carvedilol treatment (P<0.05). In parallel to the change in QTd, fractional shortening also increased significantly with carvedilol therapy (16±3% at baseline vs. 20±3% after the 2nd month and 21±3% after the 16th month; both P<0.001 compared to baseline). The clinical status of the patients also got better with carvedilol therapy. Three patients who were in NYHA Class III at study entry improved to Class II and two patients who were in Class II improved to Class I at the end of 16th month.


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  		Table 1 The QT intervals and QT dispersion values at baseline and after 2 and 16 months of carvedilol therapy

 
When the study population was subdivided into two groups depending on the etiology of CHF (ischemic vs. non-ischemic dilated cardiomyopathy) and the QT data were reanalyzed, we observed the same trend of change in all of the parameters evaluated. In the non-ischemic group the QTd, which was 78±25 ms at inclusion, decreased significantly to 39±3.5 ms at the 16th month (P<0.01). Similarly, the baseline QTd was 86±17 ms in the ischemic group, and decreased significantly to 43±5 ms after 16 months of carvedilol therapy (P<0.01).

The mean daily dose of carvedilol was 34±15 mg (range 12.5–50 mg). No significant correlation was found between the carvedilol dose and the percent decrease in QTd (P>0.05).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
Evidence from several studies supports the role of increased repolarization heterogeneity in the genesis of reentry and malignant ventricular arrhythmias [7,15]. QT dispersion is a non-invasive marker of inhomogeneity of myocardial repolarization and prolonged QTd has been reported to predict sudden death in patients with coronary artery disease, hypertrophic cardiomyopathy and long QT syndrome [12,13,16]. In addition to those diseases, previous studies also indicated significantly increased QTd values in patients with CHF [8]. Although there are doubts related to the pathophysiological meaning of QTd and limitations in its methodology, QTd is still accepted as a valuable marker in arrhythmogenic diseases. Furthermore, some authors suggested the QTd as a marker for predicting drug efficiency on mortality [9]. However, the data related to the effects of carvedilol therapy on QT intervals and QTd values are limited.

In a retrospective case control study, Bonnar et al. [8] compared the QTd and QTcd values in 25 patients with impaired left ventricular systolic function to those of 100 control subjects. A significant increase was noted in QTd and QTcd values in patients with impaired left ventricular systolic function than controls. In addition, those using beta-blocker agents had lower QTd values than non-users, suggesting the possibility of a reduction in QTd as an important antiarrhythmic mechanism of beta-blockade. However, this study compared the beta-blocker users to non-users and did not specifically address the effect of the beta-blocker on QTd in the same patient.

Jepson et al. [17] investigated the effects of carvedilol therapy on QTd in 35 patients with CHF. In addition to the conventional therapy for CHF, the patients received carvedilol at a dose of 25 mg bid and QTd and QTcd values were evaluated at study entry and after 4 weeks. Carvedilol resulted in a significant reduction in QTd and QTcd values in addition to the significant decrease in heart rate. They noted a significant increase in QTcmin values, whereas the QTcmax remained unaltered. Our findings were consistent with this study, however the reduction in QTd and QTcd values were not noted after the 2nd month but at the end of the 16th month. This later beneficial effect might be explained by the relatively lower dose of carvedilol we used in our study. However, to the best of our knowledge, the present study is the longest duration of follow-up with carvedilol treatment showing the beneficial effect of this agent on QTd. None of our subject's experienced malignant ventricular arrhythmias and echocardiographic parameters ameliorated. Only one patient died suddenly at home in the 2nd month before the maintenance period, but the reason for death could not be clarified.

Several mechanisms might be responsible for the prolonged QTd in CHF and its reduction with carvedilol therapy. The etiology of increased QTd in patients with CHF includes sympathetic overactivity, alterations in excitation contraction coupling and myocardial fibrosis [18,19]. The reduction in QTd under carvedilol treatment may be partly due to adrenergic blocking effects of this agent. However, chronic ACE inhibitor treatment in patients with CHF is also associated with a reduction in sympathetic activity [18] and it was shown that treatment with enalapril and ramipril reduced QTd in patients with symptoms of CHF due to ischemic heart disease [20,21]. However, in the present study, carvedilol treatment resulted in a significant decrease in QTd despite the pre-existing ACE inhibitor treatment. This may be due to the fact that ACE inhibitor treatment might incompletely block sympathetic activity, whereas carvedilol provides a more complete blockade. Furthermore, carvedilol has been shown to regulate sympathovagal interaction in CHF [22].

Carvedilol effectively inhibits neurohumoral pathways in CHF. It blocks the renin–angiotensin system via beta adrenoreceptors, and blocks almost completely the sympathetic nervous system activity via beta1, beta-2 and alpha-1 adrenoreceptors [23]. Furthermore, it reduces endothelin-1 levels [24]. Anti-ischemic action of carvedilol; inhibition of neutrophil function and free oxygen radical formation; antiapoptotic action; and inhibition of chronic remodeling of the myocardium indirectly prevent the potent inducers of arrhythmia in CHF patients [25–29]. It is likely that all of these factors contribute to the observed homogenization of the ventricular repolarization process. Amelioration of the underlying condition and of the distorted myocardial structure certainly plays an important role in the diminution of QTd and may be the explanation of the late beneficial effects of carvedilol on the QTd in CHF.

Another possible explanation is that, the observed reduction in QTd with carvedilol may be the expression of a direct and a unique antiarrhythmogenic effect of carvedilol. However, the exact mechanism(s) underlying the reduction of QTd with carvedilol treatment is unknown and needs to be clarified with studies including those based on microelectrode techniques investigating transmembrane activity of myocardial cells.

It is not possible to conclude from the currently available data whether the reduction in QTd with carvedilol is limited to this drug or a class effect of any beta-blocker. The only report specifically addressing this issue is by Fesmire et al. [30] who retrospectively examined the ECGs of 35 patients with non-ischemic dilated cardiomyopathy and compared the effects of selective vs. non-selective beta blockade on QTd. Of the 35 patients included in the study 12 patients were on metoprolol, eight patients were on bucindolol and six patients were on carvedilol for at least 3 months, while nine patients did not receive any beta-blockers. Although the power of the study is limited due to the small sample size in each medication subgroup, this study indicated no difference between beta1-selective metoprolol and the non-selective agents bucindolol and carvedilol in reducing QTd. Therefore, the reduction of QTd observed in a small number of studies including our study might be a group effect of beta-blockers. However, such an observation needs to be confirmed with more powerful studies before a conclusion can be made. Although, ACE inhibitors and diuretics were also shown to reduce QTd, it is unlikely that the reduction in QTd observed in this study is due to the effect of these drugs, because patients were administered carvedilol in addition to conventional CHF treatment and there was no change in the administration of these drugs during the follow-up period.

The major limitations of our study are the small sample size and the lack of a control group. However, with this design everyone served as his/her own control with stable concomitant medications throughout the study.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
This study suggests that long-term carvedilol therapy in CHF patients considerably decreases QTd, which is a potent predictor of susceptibility to ventricular arrhythmias. This antiarrhythmic effect of carvedilol, in addition to the improvement in left ventricular function, may have a significant impact on mortality benefit of carvedilol. However, the mechanism(s) underlying the reduction in QTd by carvedilol need to be clarified with more powerful studies.


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

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